CETP activity inhibitor

ABSTRACT

The present invention provides a CETP activity inhibitor comprising as an active ingredient a compound represented by the formula (I):  
                 
 
     wherein R represents a straight chain or branched alkyl group; a straight chain or branched alkenyl group; a lower haloalkyl group; a substituted or unsubstituted cycloalkyl group; a substituted or unsubstituted cycloalkenyl group; a substituted or unsubstituted cycloalkylalkyl group; a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group, X 1 , X 2 , X 3 , and X 4  may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower haloalkyl group; a lower alkoxy group; a cyano group; a nitro group; an acyl group; or an aryl group, Y represents —CO— or —SO 2 —, and Z represents a hydrogen atom or a mercapto-protecting group, or a prodrug compound, a pharmaceutically acceptable salt, or hydrate or solvate thereof. The compounds represented by the formula (I) can increase HDL and at the same time decrease LDL through selective inhibition of CETP activity and, therefore, is expected to be useful as a new type of a preventive or therapeutic agent for atherosclerosis or hyperlipidemia.

TECHNICAL FIELD

[0001] This invention relates to a novel CETP activity inhibitor whichcomprises as an active ingredient a compound having abis-(2-aminophenyl) disulfide structure or a 2-amino-phenylthiostructure and more particularly to a pharmaceutical composition fortreating or preventing atherosclerosis or hyperlipidemia. This inventionalso relates to a compound having a bis-(2-aminophehyl) disulfidestructure or a 2-aminophenylthio structure, a prodrug compound, apharmaceutically acceptable salt, hydrates or solvates of thesecompounds.

BACKGROUND ART

[0002] From the results of many epidemiological studies, it has beenconsidered that there exists certain relation between atheroscleroticdiseases and serum lipoprotein. For example, Badimon et al. (J. Clin.Invest. 85, 1234-1241 (1990)) reported that not only the prevention ofdevelopment but also regression of atherosclerotic lesions were observedafter intravenous injection of fractions containing HDL (high densitylipoprotein) and VHDL (very high density lipoprotein) tocholesterol-loaded rabbits. Thus, regarding the relation betweenatherosclerotic diseases and serum lipoproteins, it is expected that HDLand VHDL may have antiatherosclerotic activity.

[0003] Recently, it has been elucidated that there are proteins thattransfer lipids among serum lipoproteins, i.e., CETP (cholesterol estertransfer protein). The presence of CETP was first indicated by Nicholsand Smith in 1965 (J. Lipid Res. 6, 206 (1965)). cDNA of the protein waslater cloned by Drayna et al. in 1987. Molecular weight of the proteinas glycoprotein is 74,000 Da. It is about 58,000 Da after completeremoval of sugar chain. cDNA of this protein is composed of 1656nucleotide residues and codes for 476 amino acids following signalpeptide of 17 amino acid residues. Since around 44% of these amino acidsare hydrophobic, the protein is highly hydrophobic and liable to beinactivated by oxidation. CETP is synthesized in organs like liver,spleen, adrenal, fat tissue, small intestine, kidney, skeletal muscle,and myocardium. It has been confirmed that CETP is synthesized in cellslike macrophages derived from human monocytes, B lymphocytes, fat cells,small intestinal epithelial cells, CaCo₂ cells, and liver cells (forexample, HepG2 cells derived from human hepatoma cells). In addition tothese tissues, it is present in cerebrospinal fluid and seminal fluid,too. The presence is also confirmed in culture media of neuroblastomaand neuroglioma cells, and in chorioid plexus of sheep.

[0004] It has become apparent that CETP participates in metabolism ofall the lipoproteins in vivo and plays important roles in reversetransfer system of cholesterol. It attracted attention as a system thatprevents the accumulation of cholesterol into peripheral cells andfunctions as protective mechanism against atherosclerosis. In relationto HDL, which plays important roles in the reverse transfer system ofcholesterol, a great number of epidemiological studies have shown that adecrease in CE (cholesterol esters) of HDL in blood represents one ofthe risk factors for coronary artery diseases. Activity of CETP differdepending on the species of animals and it has become apparent thatcholesterol load does not bring about atherosclerosis in animals withlow CETP activity, while it is easily produced in animals with high CETPactivity. Absence of CETP results in high HDL-emia+low LDL (low densitylipoprotein)-emia and brings about a state resistant to atherosclerosis.Thus, the importance of CETP as mediators of transfer of CE in HDL toblood LDL has become recognized in addition to the importance of HDL inblood.

[0005] Free cholesterol (FC) synthesized in the liver and secretedtherefrom is taken up into very lowd ensity lipoprotein (VLDL). Next,VLDL is metabolized in the blood to LDL via intermediate densitylipoprotein (IDL) by the action of lipoprotein lipase (LPL) and livertriglyceride lipase (HTGL). LDL is taken up to peripheral cells mediatedby LDL receptor and, thus, FC is supplied to the cells.

[0006] Contrary to this flow from the liver to peripheral cells, thereexists another flow of cholesterol from peripheral cells to the livercalled cholesterol reverse transfer system. FC accumulated in peripheralcells is extracted by HDL, esterified on HDL through the action of LCAT(Lecithin: cholesterol acyltransferase) to form CE, transferred to thehydrophobic core portion of HDL, and HDL becomes matured to globular HDLparticles. CE in HDL is transferred to apoB-containing lipoproteins suchas VLDL, IDL, and LDL by CETP present in the blood. In exchange, TG istransferred to HDL in mole ratio of 1:1. CE that is transferred toapoB-containing lipoprotein is taken up by the liver via LDL receptor onit and, thus, cholesterol is transferred indirectly to the liver. Thereis mechanisms, too, by which HDL becomes CE-rich, apoproteinE-containing HDL by taking up apoprotein E secreted by macrophages andthe like, which is then taken up directly to the liver via LDL receptoror remnant receptor. In another, the liver cells do not take up HDLparticles, but take up selectively only CE in HDL. In still another, HDLparticles are taken up by the liver cells via so-called HDL receptor.

[0007] In a state, in which CETP activity is augmented, CE in HDL isdecreased and CE in VLDL, IDL and LDL is increased due to augmentationof CE transfer from HDL. Increases in uptake of IDL and LDL to the liverresult in down-regulation of LDL receptor and increases in LDL in theblood. In contrast, in a state of CETP deficiency, HDL removescholesterol from peripheral cells with the aid of LCAT, increases itssize gradually and acquires apoE. HDL that becomes apoE-rich is taken upby the liver via LDL receptor of the liver and catabolized. However, asthe operation of this mechanism is not adequate in the human, retentionof large HDL in the blood occurs and, as a result, cholesterol pool inthe liver becomes smaller. LDL receptor becomes up-regulated and LDL isdecreased.

[0008] Hence, by selectively inhibiting CETP, it is possible to decreaseIDL, VLDL, and LDL that accelerate atherosclerosis and increase HDL thatexhibits inhibitory action. Thus, it is anticipated that hithertonon-existent drugs useful for prevention or therapy of atherosclerosisor hyperlipidemia may be provided.

[0009] Very recently there have been reports on chemical compounds thataim at inhibition of such CETP activity.

[0010] For example, in Biochemical and Biophysical ResearchCommunications ZZS, 42-47 (1996), dithiodipyridine derivatives andsubstituted dithiobenzene derivatives are disclosed as compounds capableof inactivating CETP through modification of cysteine residues. However,the literature neither discloses nor suggests the compounds such asthose of the present invention which have a bis-(2-aminophenyl)disulfide structure or a 2-aminophenylthio structure.

[0011] WO95/06626 discloses Wiedendiol-A and Wiedendiol-B as CETPactivity inhibitors, but there is no description suggesting thecompounds of the present invention.

[0012] Furthermore, in JP-B-Sho 45-11132, JP-B-Sho 45-2892, JP-B-Sho45-2891, JP-B-Sho 45-2731, and JP-B-Sho 45-2730, mercaptoanilidessubstituted with higher fatty acids such as o-isostearoylaminothiophenol are disclosed. However, in these publications, theatheroscleros is-preventing action is only referred to and there is nodescription of test examples that substantiate the action. There is alsono description of CETP inhibitory activity. Nor is there descriptionsuggestive of compounds of the present invention.

[0013] There are several reports on the compounds having abis-(2-aminophenyl) disulfide structure or a 2-aminophenylthio structuresimilar to those of the present application of invention.

[0014] For example, WO96/09406 discloses disulfide compounds such as2-acetylaminophenyl disulf ide and the like. However, the compounds ofthe publication are the ones that are useful for retrovirus, i.e.,HIV-1, and usefulness as regards inhibitors of CETP activity has notbeen disclosed. There also is no description suggestive of theusefulness.

[0015] In JP-A-Hei 8-253454, diphenyl disulfide compounds such as2,2′-di(pyrimidylamino)diphenyldisulfideandthe likearedisclosed.However, the compounds in this publication are the ones that haveinhibitory action on production of IL-1β and on release of TNFα andthere are no disclosure as regards the usefulness as inhibitors of CETPactivity. There is even no description suggestive of the usefulness.

[0016] In JP-A-Hei 2-155937, bis-(acylaminophenyl) disulfide compoundssuch as 2,2′-diacetylaminodiphenyl disulfide and the like are disclosed.However, the compounds in this publication relates to the method ofmaking vulcanized rubber filled with carbon black and there are nodisclosure as regards the usefulness as inhibitors of CETP activity.There is also no description suggestive of the usefulness. In the claimsrecited in the publication, C₁-C₁₂ cycloalkyl and cycloalkenyl aredefined as R⁹ and R¹⁰, and as specific examples cyclohexyl andcyclohexenyl are described. However, in the publication no example thatsubstantiates the use of the compound is shown and there is nodescription of the general method of production of the compounds.

[0017] JP-A-Hei 2-501772 discloses acylamino phenyl disulfidederivatives such as o-pivaloylaminophenyl disulfide and the like asintermediates for production of pyrazolone photocoupler. However, theinvention described in this publication relates to the photo-element andnot suggestive of the present invention. This publication also describes2-cyclohexane carbonylamino phenylthio group as an example ofcoupling-off group of the coupler, but there is no description ofexamples that substantiate the use of the compound.

[0018] JP-A-Hei 8-171167 discloses thiophenol derivatives or disulfidederivatives such as 2-acetylamino thiophenol. However, the inventiondescribed in this publication relates to the silver halide emulsion andnot suggestive of the present invention.

[0019] In JP-A-Hei 4-233908, disulfide derivatives such asbis-(2-acetoamidephenyl) disulfide and the like are disclosed. However,the compounds of this publication is disclosed as chain transfer agentsand, thus, the publication does not suggest the present invention. Asspecific examples of R₃ in X,Y, a cyclohexyl group is disclosed, but theexample substantiating the use and the general method of production arenot described.

[0020] JP-A-Sho 63-157150 discloses amidophenyl disulfide derivativessuch as o-pivalamidophenyl disulfide and the like as stabilizers.However, the invention of this publication relates to photo-element andis not suggestive of the present invention. In the claim recited in thispublication, a cycloalkyl group is defined as R in the substituents V orY of the stabilizer compounds, but the example substantiating the useand the general method of production are not described.

[0021] Bis-(amidophenyl) disulfide derivatives are also disclosed inJP-A-Hei 8-59900, JP-A-Hei 7-258472, JP-A-Hei 7-224028, JP-A-Hei7-49554, JP-A-Hei 6-19037, JP-A-Hei 6-19024, JP-A-Hei 3-226750, JP-A-Hei2-284146, JP-A-Hei 2-23338, JP-A-Hei 1-321432, JP-A-Hei 1-278543, andJP-B-Sho 47-357786. However, none of them discloses usefulness asinhibitors of CETP activity and there is no description suggestive ofthe usefulness.

DISCLOSURE OF THE INVENTION

[0022] As described above, the present inventors studied ardently inorder to provide the compounds that selectively inhibit CETP activityand, as a result, found compounds useful as novel preventive ortherapeutic agents of atherosclerosis or hyperlipidemia with new actionmechanism which could increase HDL and at the same time decrease LDL,thereby completing the present invention.

[0023] The present invention relates to the compounds and medicaments asshown in the following (1) to (19) which have CETP activity inhibitoryeffect.

[0024] (1) A CETP activity inhibitor comprising as an active ingredienta compound represented by the formula (I):

[0025] wherein

[0026] R represents

[0027] a straight chain or branched C₁₋₁₀ alkyl group;

[0028] a straight chain or branched C₂₋₁₀ alkenyl group;

[0029] a halo-C₁₋₄ lower alkyl group;

[0030] a substituted or unsubstituted C₃₋₁₀ cycloalkyl group;

[0031] a substituted or unsubstituted C₁₋₈ cycloalkenyl group;

[0032] a substituted or unsubstituted C₃₋₁₀ cycloalkyl C₁₀ alkyl group;

[0033] a substituted or unsubstituted aryl group;

[0034] a substituted or unsubstituted aralkyl group; or

[0035] a substituted or unsubstituted 5- or 6-membered heterocyclicgroup having 1-3 nitrogen, oxygen or sulfur atoms,

[0036] X₁, X₂, X₃, and X₄ may be the same or different and represents

[0037] a hydrogen atom;

[0038] a halogen atom;

[0039] a C₁₋₄ lower alkyl group;

[0040] a halo-C₁₋₄ lower alkyl group;

[0041] a C₁₋₄ lower alkoxy group;

[0042] a cyano group;

[0043] a nitro group;

[0044] an acyl group; or

[0045] an aryl group,

[0046] Y represents

[0047] —CO—; or

[0048] —SO₂, and

[0049] Z represents

[0050] a hydrogen atom; or

[0051] a mercapto-protecting group,

[0052] a prodrug compound, a pharmaceutically acceptable salt, hydrate,or solvate thereof.

[0053] (2) A CETP activity inhibitor comprising as an active ingredientthe compound described in the above (1), wherein

[0054] R represents

[0055] a straight chain or branched C₁₋₁₀ alkyl group;

[0056] a straight chain or branched C₂₋₁₀ alkenyl group;

[0057] a halo-C₁₋₄ lower alkyl group substituted with 1-3 halogen atomsselected from fluorine, chlorine, and bromine;

[0058] a C₃₋₁₀ cycloalkyl group, a C₅₋₈ cycloalkenyl group, or a C₃ ₁₀cycloalkyl C₁₋₁₀ alkyl group, each of which may have 1-4 substituentsselected from the group consisting of

[0059] a straight chain or branched C₁₋₁₀ alkyl group,

[0060] a straight chain or branched C₂₋₁₀ alkenyl group,

[0061] a C₃₋₁₀ cycloalkyl group,

[0062] a C₅₋₈ cycloalkenyl group,

[0063] a C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group,

[0064] an aryl group selected from phenyl, biphenyl, and naphthyl,

[0065] an oxo group, and

[0066] an aralkyl group having an aryl group selected from phenyl,biphenyl, and naphthyl; or

[0067] an aryl, aralkyl, or 5- or 6-membered heterocyclic group with 1-3nitrogen, oxygen or sulfur atoms, each of which may have 1-4substituents selected from the group consisting of

[0068] a straight chain or branched C₁₋₁₀ alkyl group,

[0069] a straight chain or branched C₂₋₁₀ alkenyl group,

[0070] a halogen atom selected from fluorine, chlorine, and bromine,

[0071] a nitro group, and

[0072] a halo-C₁₋₄ lower alkyl group having a halogen atom selected fromfluorine, chlorine, and bromine;

[0073] Z represents

[0074] a hydrogen atom;

[0075] a mercapto-protecting group selected from the group consisting of

[0076] a C₁₋₄ lower alkoxymethyl group,

[0077] a C₁₋₄ lower alkylthiomethyl group,

[0078] an aralkyloxymethyl group having an aryl group selected fromphenyl, biphenyl, and naphthyl,

[0079] an aralkylthiomethyl group having an aryl group selected fromphenyl, biphenyl, and naphthyl,

[0080] a C₃₋₁₀ cycloalkyloxymethyl group,

[0081] a C₅₋₈ cycloalkenyloxymethyl group,

[0082] a C₃₋₁₀ cycloalkyl C₁,lo alkoxymethyl group,

[0083] an aryloxymethyl group having an aryl group selected from phenyl,biphenyl, and naphthyl,

[0084] an arylthiomethyl group having an aryl group selected fromphenyl, biphenyl, and naphthyl,

[0085] an acyl group,

[0086] an acyloxy group,

[0087] an aminocarbonyloxymethyl group,

[0088] a thiocarbonyl group, and

[0089] a thio group,

[0090] a prodrug compound thereof, a pharmaceutically acceptable salt,hydrate, or solvate thereof.

[0091] (3) A CETP activity inhibitor comprising as an active ingredientthe compound as described in the above (2), which is represented by theformula (1-1):

[0092] wherein R, X₁, X₂, X₃, X₄, and Y are the same as inthe above (2)and

[0093] Z₁ represents

[0094] a hydrogen atom;

[0095] a group represented by the formula

[0096] wherein R, X₁, X₂, X₃, X₄, and Y are the same as described above;

[0097] —Y₁R₁,

[0098] wherein Y₁ represents —CO—; or

[0099] —CS—, and

[0100] R₁ represents

[0101] a substituted or unsubstituted straight chain or branched C₁₋₁₀alkyl group;

[0102] a C₁₋₄ lower alkoxy group;

[0103] a C₁₋₄ lower alkylthio group;

[0104] a substituted or unsubstituted amino group;

[0105] a substituted or unsubstituted ureido group;

[0106] a substituted or unsubstituted C₃₋₁₀ cycloalkyl group;

[0107] a substituted or unsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀ alkylgroup;

[0108] a substituted or unsubstituted aryl group;

[0109] a substituted or unsubstituted aralkyl group;

[0110] a substituted or unsubstituted arylalkenyl group;

[0111] a substituted or unsubstituted arylthio group;

[0112] a substituted or unsubstituted 5- or 6-membered heterocyclicgroup having 1-3 nitrogen, oxygen, or sulfur atoms; or

[0113] a substituted or unsubstituted 5- or 6-membered heteroarylalkylgroup; or

[0114] —S—R₂,

[0115] wherein R₂ represents

[0116] a substituted or unsubstituted C₁₋₄ lower alkyl group; or

[0117] a substituted or unsubstituted aryl group,

[0118] a prodrug compound, a pharmaceutically acceptable salt, hydrate,or solvate thereof.

[0119] (4) A CETP activity inhibitor comprising as an active ingredientthe compound as described in the above (3), wherein

[0120] R₁ represents

[0121] a straight chain or branched C₁₋₁₀ alkyl group which may have 1-3substituents selected from the group consisting of

[0122] a halogen atom selected from fluorine, chlorine, and bromine,

[0123] a C₁₋₄ lower alkoxy group,

[0124] an amino group that may be substituted with a C₁₋₄ lower alkyl,acyl, or hydroxyl group,

[0125] a C₁₋₄ lower alkylthio group,

[0126] a carbamoyl group,

[0127] a hydroxyl group,

[0128] an acyl group,

[0129] an acyloxy group having an acyl group,

[0130] a carboxyl group, and

[0131] an aryloxy group that may be substituted with a halogen atomselected from fluorine, chlorine, and bromine;

[0132] a C₁₋₄ lower alkoxy group;

[0133] a C₁₋₄ lower alkylthio group;

[0134] an amino or ureido group that may have 1-2 substituents selectedfrom the group consisting of

[0135] a C₁₋₄ lower alkyl group,

[0136] a hydroxyl group,

[0137] an acyl group, and

[0138] an aryl group that may be substituted with a lower C₁₋₄ alkoxygroup;

[0139] a C₃₋₁₀ cycloalkyl or C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group that mayhave substituents selected from the group consisting of

[0140] a straight or branched C₁₋₁₀ alkyl group,

[0141] a C₃₋₁₀ cycloalkyl group,

[0142] a C₅₋₈ cycloalkenyl group,

[0143] an aryl group,

[0144] an amino group,

[0145] a C₁₋₄ lower alkylamino group having a C₁₋₄ lower alkyl group,and

[0146] an acylamino group having an acyl group;

[0147] an aryl group, an aralkyl group, an arylalkenyl group, or anarylthio group, each of which may have 1-4 substituents selected fromthe group consisting of

[0148] a C₁₋₁₀ alkyl group,

[0149] a halogen atom selected from fluorine, chlorine, and bromine,

[0150] a nitro group,

[0151] a hydroxyl group,

[0152] a C₁₋₄ lower alkoxy group,

[0153] a C₁₋₄ lower alkylthio group,

[0154] an acyl group,

[0155] a halo- C₁₋₄ lower alkyl group having a halogen atom selectedfrom fluorine, chlorine, and bromine, and

[0156] an amino group that may be substituted with a C₁₋₄ lower alkyl oracyl group;

[0157] a 5- or 6-membered heterocyclic group having 1-3 nitrogen, oxygenor sulfur atoms or a 5- or 6-membered heteroarylalkyl group that mayhave 1-4 substituents selected from the group consisting of

[0158] a straight chain or branched C₁₋₁₀ alkyl group,

[0159] a halogen atom selected from fluorine, chlorine, and bromine,

[0160] an acyl group,

[0161] an oxo group, and

[0162] an halo-C₁₋₄ lower alkyl group having a halogen atom selectedfrom fluorine, chlorine, and bromine; and

[0163] R₂ represents

[0164] a C₁₋₄ lower alkyl group that may have 1-3 substituents selectedfrom the group consisting of

[0165] a C₁₋₄ lower alkoxy groups,

[0166] an amino group that may be substituted with a C₁₋₄ lower alkyl oracyl group,

[0167] a C₁₋₄ lower alkylthio group,

[0168] a carbamoyl group,

[0169] a hydroxyl group,

[0170] a carboxyl group,

[0171] an acyl group, and

[0172] a 5- or 6-membered heterocyclic group having 1-3 nitrogen,oxygen, or sulfur atoms; or

[0173] an aryl group that may have 1-4 substituents selected from thegroup consisting of

[0174] a C₁₋₄ lower alkyl group,

[0175] a halogen atom selected from fluorine, chlorine, and bromine,

[0176] a nitro group,

[0177] a hydroxyl group,

[0178] a C₁₋₄ lower alkoxy group,

[0179] a C₁₋₄ lower alkylthio group,

[0180] an acyl group,

[0181] an amino group that may be substituted with a C₁₋₄ lower alkyl oracyl group, and

[0182] a halo-C₁₋₄ lower alkyl group having a halogen atom selected fromfluorine, chlorine, and bromine,

[0183] a prodrug compound, a pharmaceutically acceptable salt, hydrate,or solvate thereof.

[0184] (5) A CETP activity inhibitor comprising as an active ingredientthe compound as described in the above (1), which is selected from thegroup consisting of

[0185] bis-[2-(pivaloylamino)phenyl] disulfide;

[0186] bis-[2-(2-propylpentanoylamino)phenyl]disulfide;

[0187] bis-[2-(1-methylcyclohexanecarbonylamino)phenyl] disulfide;

[0188] bis-[2-(1-isopentylcyclopentanecarbonylamino)phenyl] disulfide;

[0189] bis-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] disulfide;

[0190] N-(2-mercaptophenyl)-2,2-dimethylpropionamide;

[0191] N-(2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide;

[0192] N-(2-mercaptophenyl)-1-methylcyclohexanecarboxamide;

[0193] N-(2-mercaptophenyl)-1-isopentylcyclopentanecarboxamide;

[0194] N-(2-mercaptophenyl)-1-isopropylcyclohexanecarboxamide;

[0195]N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide;

[0196]N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclopentanecarboxamide;

[0197] N-(2-mercapto-5-methylphenyl)-1-isopentylcyclohexanecarboxamide;

[0198] N-(2-mercapto-4-methylphenyl)-1-isopentylcyclohexanecarboxamide;

[0199] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thioacetate;

[0200] S-[2-(1-methylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

[0201] S-[2-(pivaloylamino)phenyl]phenylthioacetate;

[0202] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

[0203] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-3-phenylthiopropionate;

[0204] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]3-pyridinethiocarboxylate;

[0205] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]chlorothioacetate;

[0206] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]methoxythioacetate;

[0207] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] thiopropionate;

[0208] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]phenoxy-thioacetate;

[0209] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;

[0210] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate;

[0211] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclopropanethiocarboxylate;

[0212] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-4-carbamoylthiobutyrate;

[0213] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-hydroxy-2-methylthiopropionate;

[0214] S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

[0215] S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl] thioacetate;

[0216] S-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

[0217] S-[4,5-dichloro-2-(1-isopentylcyclopentanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

[0218]S-[2-(1-isopentylcyclohexanecarbonylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;

[0219] O-methyl S-[2-(1-isopentylcyclohexanecarbonylamino)phenylmonothiocarbonate;

[0220] S-[2-(1-methylcyclohexanecarbonylamino)phenyl] S-phenyldithiocarbonate;

[0221] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]N-phenylthiocarbamate;

[0222] S-[2-(pivaloylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;

[0223] S-[4,5-dichloro-2-(1-cyclopropylcyclohexanecarbonylamino) phenyl]2,2-dimethylthiopropionate;

[0224] S-[4,5-dichloro-2-(2-cyclohexylpropionylamino)phenyl]2,2-dimethylthiopropionate;

[0225] S-[4,5-dichloro-2-(1-pentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

[0226] S-[4,5-dichloro-2-(1-cyclopropylmethylcyclohexanecarbonylamino)phenyl] 2,2-dimethylthiopropionate;

[0227]S-[4,5-dichloro-2-(1-cyclohexylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

[0228] S-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

[0229] S-[4,5-dichloro-2-(1-isopentylcycloheptanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

[0230] S-[4,5-dichloro-2-(1-isopentylcyclobutanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

[0231] S-[2-(1-isopentylcyclohexanecarbonylamino)-4-nitrophenyl]2,2-dimethylthiopropionate;

[0232] S-[4-cyano-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

[0233] S-[4-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

[0234] S-[5-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

[0235] S-[4-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

[0236] S-[4,5-difluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

[0237] S-[5-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

[0238] bis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]disulfide;

[0239] 2-tetrahydrofurylmethyl 2-(1-isopentylcyclohexanecarbonylamino)phenyl disulfide;

[0240] N-(2-mercaptophenyl)-1-ethylcyclohexanecarboxamide;

[0241] N-(2-mercaptophenyl)-1-propylcyclohexanecarboxamide;

[0242] N-(2-mercaptophenyl)-1-butylcyclohexanecarboxamide;

[0243] N-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide;

[0244] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclohexanethiocarboxylate;

[0245] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] thiobenzoate;

[0246] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]5-carboxythiopentanoate;

[0247] S-[2-(1-isopentylcyclohexanecarbonylamino)-4-methylphenyl]thioacetate;

[0248] bis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]disulfide;

[0249] N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide;

[0250] S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-methylthiopropionate;

[0251] S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;

[0252] S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]1-acetylpiperidine-4-thiocarboxylate;

[0253] S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]thioacetate;

[0254] S-[2-[l-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2,2-dimethylthiopropionate;

[0255] S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]methoxythioacetate;

[0256] S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-hydroxy-2-methylthiopropionate;

[0257] S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]4-chlorophenoxythioacetate;

[0258] S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate; and

[0259]S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]-1-acetyl-piperidine-4-thiocarboxylate,

[0260] a prodrug compound, a pharmaceutically acceptable salt, hydrate,or solvate thereof.

[0261] (6) A prophylactic or therapeutic agent for hyperlipidemiacomprising as an active ingredient the compound as described in theabove in (1)-(5), a prodrug compound, a pharmaceutically acceptablesalt, hydrate, or solvate thereof.

[0262] (7) A prophylactic or therapeutic agent for atherosclerosiscomprising as an active ingredient the compound as described in theabove in (1)-(5), a prodrug compound, a pharmaceutically acceptablesalt, or hydrate or solvate thereof.

[0263] (8) A Compound represented by the formula (1-2):

[0264] wherein R′ represents

[0265] a substituted or unsubstituted C₃₋₁₀ cycloalkyl group or

[0266] a substituted or unsubstituted C₅₋₈ cycloalkenyl group;

[0267] X₁, X₂, X₃, and X₄ are as in the above (1); and

[0268] Z₁′ represents

[0269] a hydrogen atom;

[0270] a group represented by the formula:

[0271] wherein R′, X₁, X₂, X₃, and X₄ are as described above;

[0272] —Y₁R₁,

[0273] wherein Y₁ and R₁ are the same as in the above (3) or —S—R₂,

[0274] wherein R₂ is the same as in the above (3),

[0275] a prodrug compound, a pharmaceutically acceptable salt,hydrate,or solvate thereof.

[0276] (9) A compound as described above in (8), which is represented bythe formula (1-3):

[0277] wherein R″ represents

[0278] a 1-substituted-C₃₋₁₀ cycloalkyl group or

[0279] a 1-substituted-C₅₋₈, cycloalkenyl group;

[0280] X₁, X₂, X₃, and X₄ are the same as in the above (1); and

[0281] Z₁″ represents

[0282] a hydrogen atoms;

[0283] a group represented by the formula:

[0284] wherein R″, X₁, X₂, X₃, and X, are as described above;

[0285] —Y,R1,

[0286] wherein Y₁ and R₁ are the same as in the above (3); or

[0287] —S—R₂,

[0288] wherein R₂ is the same as in the above (3),

[0289] a prodrug compound, a pharmaceutically acceptable salt,hydrate,or solvate thereof.

[0290] (10) A compound as described in the above (8), which isrepresented by the formula (II):

[0291] wherein R′, X₁, X₂, X₃, and X₄ are the same as in the above (8),a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

[0292] (11) A compound as described in the above (9), which isrepresented by formula (II-1):

[0293] wherein R″, X₁, X₂, X₃, and X₄ are the same as in the above (9),a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

[0294] (12) A compound as described in the above (8), which representedby the formula (III):

[0295] wherein R′, X₁, X₂, X₃, and X₄ are the same as in the above (8),a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

[0296] (13) A compound as described in the above (9), which isrepresented by formula (III-1):

[0297] wherein R″, X₁, X₂, X₃, and X₄ are the same as in the above (9),a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

[0298] (14) A compound as described in the above (8), which isrepresented by formula (IV):

[0299] wherein R′, X₁, X₂, X₃, X₄, Y₁ and R₁ are the same as in theabove (8), a prodrug compound, a pharmaceutically acceptable salt,hydrate, or solvate thereof.

[0300] (15) A compound as described in the above (9), which isrepresented by formula (IV-1):

[0301] wherein R″, X₁, X₂, X₃, X₄, Y₁, and R₁ are the same as in theabove (9),

[0302] a prodrug compound, a pharmaceutically acceptable salt, hydrate,or solvate thereof.

[0303] (16) A compound as described in the above (8), which isrepresented by formula (V):

[0304] wherein R′, X₁, X₂, X₃, X₄, and R₂ are the same as in the above(8), a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

[0305] (17) A compound as described in the above (9), which isrepresented by formula (V-1):

[0306] wherein R″, X₁I X₂, X₃, X₄, and R₂ are the same as in the above(9), a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

[0307] (18) A compound as described in the above (8), which is selectedfrom the group consisting of

[0308] bis-[2-(1-methylcyclohexanecarbonylamino)phenyl] disulfide;

[0309] bis-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]disulfide;

[0310] bis-[2-(-isopentylcyclohexanecarbonylamino)phenyl] disulfide;

[0311] N-(2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide;

[0312] N-(2-mercaptophenyl)-1-methylcyclohexanecarboxamide;

[0313] N-(2-mercaptophenyl)-1-isopentylcyclopentanecarboxamide;

[0314] N-(2-mercaptophenyl)-1-isopropylcyclohexanecarboxamide;

[0315]N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide;

[0316]N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclopentanecarboxamide;

[0317] N-(2-mercapto-5-methylphenyl)-1-isopentylcyclohexanecarboxamide;

[0318] N-(2-mercapto-4-methylphenyl)-1-isopentylcyclohexanecarboxamide;

[0319] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] thioacetate;

[0320] S-[2-(1-methylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

[0321] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

[0322] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-3-phenylthiopropionate;

[0323] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]3-pyridinethiocarboxylate;

[0324] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]chlorothioacetate;

[0325]S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]methoxythioacetate;

[0326] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] thiopropionate;

[0327] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]phenoxythioacetate;

[0328] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;

[0329] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate;

[0330] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclopropanethiocarboxylate;

[0331] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-4-carbamoylthiobutyrate;

[0332] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-hydroxy-2-methylthiopropionate;

[0333] S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]2,2-dimethylpropionate;

[0334] S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl] thioacetate;

[0335] S-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

[0336] S-[4,5-dichloro-2-(1-isopentylcyclopentanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

[0337]S-[2-(1-isopentylcyclohexanecarbonylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;

[0338] O-methyl S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]monothiocarbonate;

[0339] S-[2-(1-methylcyclohexanecarbonylamino)phenyl] S-phenyldithiocarbonate;

[0340] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]N-phenylthiocarbamate;

[0341] S-[4,5-dichloro-2-(1-cyclopropylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

[0342] S-[4,5-dichloro-2-(1-pentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

[0343]S-[4,5-dichloro-2-(1-cyclopropylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

[0344]S-[4,5-dichloro-2-(1-cyclohexylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropioate;

[0345] S-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

[0346] S-[4,5-dichloro-2-(1-isopentylcycloheptanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

[0347] S-[4,5-dichloro-2-(1-isopentylcyclobutanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

[0348] S-[2-(1-isopentylcyclohexanecarbonylamino)-4-nitrophenyl]2,2-dimethylthiopropionate;

[0349] S-[4-cyano-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

[0350] S-[4-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

[0351] S-[5-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

[0352] S-[4-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;

[0353] S-[4,5-difluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

[0354] S-[5-fluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;

[0355] bis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]disulfide;

[0356] 2-tetrahydrofurylmethyl2-(1-isopentylcyclohexanecarbonyl-amino)phenyl disulfide;

[0357] N-(2-mercaptophenyl)-1-ethylcyclohexanecarboxamide;

[0358] N-(2-mercaptophenyl)-propylcyclohexanecarboxamide;

[0359] N-(2-mercaptophenyl)-1-butylcyclohexanecarboxamide;

[0360] N-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide;

[0361] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclohexanethiocarboxylate;

[0362] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] thiobenzoate;

[0363] S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]5-carboxythiopentanoate;

[0364] S-[2-(1-isopentylcyclohexanecarbonylamino)-4-methylphenyl]thioacetate;

[0365]bis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]-disulfide;

[0366] N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide;

[0367] S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-methylthiopropionate;

[0368] S-[2-[1-isobutylcyclohexanecarbonylamino]phenyl]2-methylthiopropionate;

[0369] S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]1-acetylpiperidine-4-thiocarboxylate;

[0370] S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]thioacetate;

[0371] S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2,2-dimethylthiopropionate;

[0372] S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]methoxythioacetate;

[0373] S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-hydroxy-2-methylpropionate;

[0374] S-(2-[1-[2-ethylbutyl)cyclohexanecarbonylamino]phenyl]4-chlorophenoxythioacetate;

[0375] S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate; and

[0376] S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]1-acetylpiperidine-4-thiocarboxylate,

[0377] a prodrug compound, a pharmaceutically acceptable salt, hydrate,or solvate thereof.

[0378] (19) A phamaceutical composition comprising as an activeingredient the compound as described in the above (8)-(18), a prodrugcompound, a pharmaceutically acceptable salt, hydrate, or solvatethereof.

[0379] (20) Use of the compound represented by the above formula (I), aprodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof, for production of a CETP activity inhibitor.

[0380] (21) Use of the compound represented by the above formula (I), aprodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof, for production of a prophylactic or therapeutic agentfor hyperlipidemia.

[0381] (22) Use of the compound represented by the above formula (I), aprodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof, for production of a prophylactic or therapeutic agentfor atherosclerosis.

[0382] (23) A method for inhibition of CETP activity comprisingadministering to patients the compound represented by the above formula(I), a prodrug compound, a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

[0383] (24) A method for prevention or therapy of hyperlipidemiacomprising administering to patients the compound represented by theabove formula (I), a prodrug compound, a pharmaceutically acceptablesalt, hydrate, or solvate thereof.

[0384] (25) A method for prevention or therapy of atherosclerosiscomprising administering to patients the compound represented by theabove formula (I), a prodrug compound, a pharmaceutically acceptablesalt, or hydrate, or solvate thereof.

[0385] The term “straight chain or branched C₁₁, alkyl group” usedherein means an alkyl group having 1-10 carbon atoms which may bestraight or branched. Specific examples thereof include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, tert-pentyl, 1-ethylbutyl, 2-ethylbutyl,1-propylbutyl, 1,1-dimethylbutyl, 1-isobutyl-3-methylbutyl,1-ethylpentyl, 1-propylpentyl, 1-isobutylpentyl, 2-ethylpentyl,2-isopropylpentyl, 2-tert-butylpentyl, 3-ethylpentyl, 3-isopropylpentyl,4-methylpentyl, 1,4-dimethylpentyl, 2,4-dimethylpentyl,1-ethyl-4-methylpentyl, hexyl, 1-ethylhexyl, 1-propylhexyl,2-ethylhexyl, 2-isopropylhexyl, 2-tert-butylhexyl, 3-ethylhexyl,3-isopropylhexyl, 3-tert-butylhexyl, 4-ethylhexyl, 5-methylhexyl,heptyl, 1-ethylheptyl, 1-isopropylheptyl, 2-ethylheptyl,2-isopropylheptyl, 3-propylheptyl, 4-propylheptyl, 5-ethylheptyl,6-methylheptyl, octyl, 1-ethyloctyl, 2-ethyloctyl, nonyl, 1-methylnonyl,2-methylnonyl, decyl, and the like groups. A straight chain or branchedalkyl group having 1-8 carbon atoms is preferred.

[0386] The term “C₁₋₄ lower alkyl group” used herein means an alkylgroup having 1-4 carbon atoms, and specifically includes methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and the likegroups.

[0387] The term “straight chain or branched C₂₋₁₀ alkenyl group” meansan alkenyl group having 2-10 carbon atoms with at least one or moredouble bonds, which may be straight or branched. Specific examplesthereof include allyl, vinyl, isopropenyl, 1-propenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-methyl-1-butenyl, crotyl,1-methyl-3-butenyl, 3-methyl-2-butenyl, 1,3-dimethyl-2-butenyl,1-pentenyl, 1-methyl-2-pentenyl, 1-ethyl-3-pentenyl, 4-pentenyl,1,3-pentadienyl, 2,4-pentadienyl, 1-hexenyl, 1-methyl-2-hexenyl,3-hexenyl, 4-hexenyl, 1-butyl-5-hexenyl, 1,3-hexadienyl, 2,4-hexadienyl,1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl,1,3-heptadienyl, 2,4-heptadienyl, 1-octenyl, 2-octenyl, 3-octenyl,4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl,3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl,9-decenyl, and the like groups. An alkenyl group having 2-8 carbonatoms, which may be straight or branched, is preferred.

[0388] The term “halogen atom” means fluorine, chlorine, and bromineatoms.

[0389] The term “halo-C₁₋₄ alkyl group” means the above-described C₁₋₄lower alkyl group substituted with 1-3 halogens, which may be the sameor different. Specific examples thereof include fluoromethyl,chloromethyl, bromomethyl, difluoromethyl, dichloromethyl,trifluoromethyl, trichloromethyl, chloroethyl, difluoroethyl,trifluoroethyl, pentachloroethyl, bromopropyl, dichloropropyl,trifluorobutyl, and the like groups. Trifluoromethyl and chloroethyl arepreferred.

[0390] The term “C₁₋₄ lower alkoxy group” means the alkoxy groupcontaining the C₁₋₄ lower alkyl group as described above. Examplesthereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, and the like groups.

[0391] The term “C₁₋₄ lower alkylthio group” means the alkylthio groupcontaining the C₁₋₄ lower alkyl group as described above. Examplesthereof include methylthio, ethylthio, propylthio, isopropylthio,butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the likegroups.

[0392] The term “C₃₋₁₀ cycloalkyl group” means a cycloalkyl group having3-10 carbon atoms, which may be monocyclic or polycyclic. Examplesthereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, octahydroindenyl, decahydronaphthyl,bicyclo[2.2.1 ]heptyl, adamantyl, and the like groups. Preferred arethose having 5-7 carbon atoms, including cyclopentyl, cyclohexyl, andcycloheptyl.

[0393] The term “C₅₋₈ cycloalkenyl group” means a cycloalkenyl grouphaving 5-8 carbon atoms with one or more double bonds on the ring.Examples thereof include cyclopentenyl, zyclohexenyl, cycloheptenyl,cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl,cyclooctadienyl, and the like groups. Preferred are those with 5-7carbon atoms, including cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0394] The term “C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group” means theabove-described straight chain or branched C₁₋₁₀ alkyl group substitutedwith the above-described C₃₋₁₀ cycloalkyl group. Specific examplesthereof include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,cyclohexyl cyclopentylmethyl, dicyclohexylmethyl, 1-cyclopentylethyl,1-cyclohexylethyl, 2-cyclopropylethyl, 2-cyclopentylethyl,2-cyclohexylethyl, 2-cycloheptylethyl, 1-cyclohexyl-1-methylethyl,1-cyclohexylpropyl, 2-cyclopentylpropyl, 3-cyclobutylpropyl,3-cyclopentylpropyl, 3-cyclohexylpropyl, 3-cycloheptylpropyl,1-cyclopropyl-1-methylpropyl, 1-cyclohexyl-2-methylpropyl,1-cyclopentylbutyl, 1-cyclohexylbutyl, 3-cyclohexylbutyl,4-cyclopropylbutyl, 4-cyclobutylbutyl, 4-cyclopentylbutyl,1-cyclohexyl-1-methylbutyl, 1-cyclopentyl-2-ethylbutyl,1-cyclohexyl-3-methylbutyl, 1-cyclopentylpentyl, 1-cyclohexylpentyl,1-cyclohexylmethylpentyl, 2-cyclohexylpentyl, 2-cyclohexylmethylpentyl,3-cyclopentylpentyl, 1-cyclohexyl-4-methylpentyl, 5-cyclopentylpentyl,1-cyclopentylhexyl, 1-cyclohexylhexyl, 1-cyclopentylmethylhexyl,2-cyclopentylhexyl, 2-cyclopropylethylhexyl, 3-cyclopentylhexyl,1-cyclohexylheptyl, 1-cyclopentyl-1-methylheptyl,1-cyclohexyl-1,6-dimethylheptyl, 1-cycloheptyloctyl, 2-cyclopentyloctyl,3-cyclohexyloctyl, 2-cyclopentylmethyloctyl, 1-cyclopentylnonyl,1-cyclohexylnonyl, 3-cyclopropylnonyl, 1-cyclopentyldecyl,1-cyclohexylundecyl, 1-cyclopentyltridecyl, 2-cyclohexyltridecyl, andthe like groups.

[0395] The “aryl group” includes phenyl, naphthyl, anthlryl,phenanthryl, biphenyl, and the like groups. Phenyl, naphthyl, andbiphenyl groups are preferred.

[0396] The “aralkyl group” means the above-described C₁₋₄ lower alkylgroup substituted with one or more aryl groups as described above.Examples thereof include benzyl, benzhydryl, trityl, phenethyl,3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl, naphthylmethyl,2-naphthylethyl, 4-biphenylmethyl, 3-(4-biphenyl) propyl, and the likegroups.

[0397] The “arylalkenyl group” means an alkenyl group having 2-4 carbonatoms substituted with the above-described aryl group. Examples thereofinclude 2-phenylvinyl, 3-phenyl-2-propenyl,3-phenyl-2-methyl-2-propenyl, 4-phenyl-3-butenyl, 2-(1-naphthyl)vinyl,2-(2-naphthyl)vinyl, 2-(4-biphenyl)vinyl, and the like groups.

[0398] The “arylthio group” means an arylthio group containing theabove-described aryl group and specifically include phenylthio,naphthylthio, and the like groups.

[0399] The “heterocyclic ring group” means 5- and 6-membered aromatic ornon-aromatic heterocyclic ring groups containing at least one or more,specifically 1-4, preferably 1-3, hetero atoms selected from nitrogen,oxygen, and sulfur atoms. Specific examples thereof include aromaticheterocyclic rings such as thiatriazolyl, tetrazolyl, dithiazolyl,oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, pyrazolyl, pyrrolyl,furyl, thienyl, tetrazinyl, triazinyl, pyrazinyl, pyridazinyl,pyrimidinyl, pyridyl, or the like groups and non-aromatic heterocyclicrings such as dioxoranyl, pyrrolidinyl, tetrahydrofuryl,tetrahydrothienyl, dithiadiazinyl, thiadiazinyl, morpholino,morpholinyl, oxazinyl, thiazinyl, piperazinyl, piperidyl, piperidino,pyranyl, thiopyranyl, or the like groups. Preferable groups are aromaticheterocyclic (heteroaryl) groups including furyl, thienyl, pyrrolyl,.pyridyl, and the like and non-aromatic heterocyclic groups containing atleast one nitrogen atom, including pyrrolidinyl, tetrahydrofuryl,piperazinyl, piperidyl, piperidino, and the like groups.

[0400] The “heteroarylalkyl group” means the above-described C₁₋₄ loweralkyl group substituted with the above-described 5- or 6-memberedaromatic heterocyclic (heteroaryl) group and specifically include2-thienylmethyl, 2-furylmethyl, 2-pyridylmethyl, 3-pyridylmethyl,2-thienyl-2-ethyl, 3-furyl-1-ethyl, 2-pyridyl-3-propyl, and the likegroups.

[0401] The “acyl group” specifically includes formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl,propioloyl, metacryloyl, crotonoyl, benzoyl, naphthoyl, toluoyl,hydroatropoyl, atropoyl, cinnamoyl, furoyl, thenoyl, nicotinoyl,isonicotinoyl, glucoloyl, lactoyl, glyceroyl, tropoyl, benzyloyl,salicyloyl, anisoyl, vaniloyl, veratoroyl, piperoniroyl, protocatechoyl,galloyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl, 1-methyl cyclohexanecarbonyl,1-isopentylcyclopentanecarbonyl, 1-isopentyl cyclohexanecarbonyl,tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl,2-(1-isopentylcyclohexanecarbonylamino)phenylthiocarbonyl, and the likegroups. Preferred are acetyl, tert-butoxycarbonyl, benzoyl,1-methylcyclohexanecarbonyl, 1-isopentylcyclopentanecarbonyl,1-isopentylcyclohexanecarbonyl, and2-(1-isopentylcyclohexanecarbonylamino)phenylthiocarbonyl.

[0402] The term “substituted or unsubstituted” of the “substituted orunsubstituted C₃₋₁₀ cycloalkyl group”, the “substituted or unsubstitutedC₅₋₈ cycloalkenyl group”, and the “substituted or unsubstituted C₃₋₁₀cycloalkyl C₁₋₁₀ alkyl group” described for R, R₁, and the like meansthat the group may be substituted with 1-4 substituents which may be thesame or different and any position may be arbitrarily substitutedwithout any limitation. Specific examples of these groups are theabove-described straight chain or branched C₁₋₁₀ alkyl group; theabove-described straight chain or branched C₂₋₁₀ alkenyl group; theabove-described C₃₋₁₀ cycloalkyl group; the above-described C₅₋₈ Hcycloalkenyl group; the above-described C₃₋₁₀ cycloalkyl C₁₋₁₀ alkylgroup; the above-described aryl group; an amino group; a C₁₋₄ loweralkylamino group such as methylamino, ethylamino, or the like groups; anacylamino group such as acetylamino, propionylamino, benzylamino, or thelike groups; an oxo group; the above-described aralkyl group; theabove-described arylalkenyl group, and the like.

[0403] The above substituents are recommended as substituents for R.Among these, preferred for R₁ are the above-described straight chain orbranched C₁₋₁₀ alkyl group, the above-described C₃₋₁₀ cycloalkyl group,the above-described C₅₋₈ cycloalkenyl group, the above-described arylgroup, and the above-described amino group.

[0404] The term “substituted or unsubstitueted” of the “substituted orunsubstitueted aryl group”, the “5- or 6-membered heterocyclic groupcontaining 1-3 nitrogen, oxygen, or sulfur atoms”, the “substituted orunsubstitueted aralkyl group”, the “substituted or unsubstituetedarylalkenyl group”, the “substituted or unsubstitueted arylthio group”,and the “substituted or unsubstitueted 5- or 6-membered heteroarylalkylgroup” described with respect to R, R₁, and the like means that thegroups may be substituted with 1-4, preferably 1-3, substituents whichmay be the same or different and any position may be arbitrarilysubstituted without particular restriction. Examples of these groupsinclude the above-described straight chain or branched C₁₋₁₀ alkylgroup, preferably a straight chain or branched C₁₋₆ aralkyl group; theabove-described straight chain or branched C₂₋₁₀alkenyl group,preferably a straight chain or branched C₂₋₆ alkenyl group; theabove-described halogen atom; a nitro group; the above-described aminogroup that may be substituted with the above-described C₁₋₄ lower alkylgroup or the above-described acyl group; a hydroxyl group; theabove-described C₁₋₄ lower alkoxy group; the above-described C₁₋₄ loweralkylthio group; the above-described halo-C₁₋₄ lower alkyl group; theabove-described acyl group; an oxo group, and the like.

[0405] The above substituents are recommended as substituents mainly forR₁. Among these, preferred for R the above-described straight chain orbranched C₁₋₆ alkyl group, the above-described halogen atom, and a nitrogroup.

[0406] The “substituted or unsubstituted” of the “substituted orunsubstituted straight chain or branched C₁₋₁₀ alkyl group” describedfor R, and the like means that the group may be substituted with 1-3substituents which may be the same or different and any position may bearbitrarily substituted without particular restriction. Examples ofthese groups are the above-described C₁₋₄ lower alkoxy group; theabove-described C₁₋₄ lower alkyl. group; the above-described amino groupthat may be substituted with an acyl or hydroxyl group; theabove-described lower C₁₋₄ alkylthio group; a carbamoyl group; ahydroxyl group; the above-described halogen atom; the above-describedacyloxy group containing an acyl group; a carboxyl group; theabove-described acyl group; the above-described aryloxy group containingan aryl group that may be substituted; and the like.

[0407] The “substituted or unsubstituted” of the “C₁₋₄ lower alkylgroup” described with respect to R₂ and the like means that the groupmay be substituted with 1-3 substituents which may be the same ordifferent and any position may be arbitrarily substituted withoutparticular restriction. Examples of the group include theabove-described C₁₋₄ lower alkoxy group; the above-described amino groupthat may be substituted with the above-described C₁₋₄ lower alkyl groupor the above-described acyl group; the above-described C₁₋₄ loweralkylthio group; a carbamoyl group; a hydroxyl group; a carboxyl group;the above-described acyl group; the above-described heterocyclic group(particularly aromatic heterocyclic groups such as thienyl ornon-aromatic heterocyclic groupr such as tetrahydrofuryl); and the like.

[0408] The term “substituted or unsubstituted” of the “substituted orunsubstituted amino group” and the “substituted or unsubstituted ireidogroup” described with respect to R, means that the groups may besubstituted with one or more, preferably 1-2, substituents which may bethe same or different and any position may be arbitrarily substitutedwithout particular restriction. Examples of these groups are theabove-described C₁₋₄ lower alkyl group; a hydroxyl group; theabove-described acyl group; the above-described aryl group which may besubstituted with the above-described C₁₋₄ lower alkoxy group; and thelike.

[0409] The “mercapto-protecting group” described with respect to z meanscommonly usedmercapto protectinggroups. Anyorganic residues that can bedissociated in vivo may be used without particular restriction. It mayform a disulfide structure, that is dimer. Examples thereof include C₁₋₄lower alkoxymethyl; C, ₄ lower alkylthiomethyl; aralkyloxymethyl;aralkylthiomethyl; C₃₋₁₀ cycloalkyloxymethyl; C., cycloalkenyloxymethyl;C₃₋₁₀ cycloalkyl C₁₋₁₀ alkoxymethyl; aryloxymethyl; arylthiomethyl;acyl; acyloxy; aminocarbonyloxymethyl; thiocarbonyl; and thio groups.Specific examples thereof include a C₁₋₄ lower alkoxymethyl group withthe above-described C₁₋₄ lower alkoxy group; a C₁₋₄ loweralkylthiomethyl group with the above-described C₁₋₄ lower alkylthiogroup; an aralkyloxymethyl group with the above-described aralkyl group;an aralkylthiomethyl group with the above-described aralkyl group; aC₃₋₁₀ cycloalkyloxymethyl group with the above-described C₃₋₁₀cycloalkyl group; a C₁₋₈ cycloalkenyloxymethyl group with theabove-described C₅₋₈ cycloalkenyl group; a C₃₋₁₀ cycloalkylC₁₋₁₀alkoxymethyl group with the above-described C₃₋₁₀ cycloalkyl C₁₋₁₀alkyl group; an aryloxymethyl group with the above-described aryl group;an arylthiomethyl group with the above-described arylthio group; an acylgroup containing the above-described substituted or unsubstitutedstraight chain or branched C₁₋₁₀ alkyl group, the above-describedhalo-C₁₋₄ lower alkyl group, the above-described C₁₋₄ lower alkoxygroup, the above-described C₁₋₄ lower alkylthio group, theabove-described substituted or unsubstituted amino group, theabove-described substituted or unsubstituted ureido group, theabove-described substituted or unsubstituted C₃₋₁₀ cycloalkyl group, theabove-described substituted or unsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀alkyl group, the above-described substituted or unsubstituted arylgroup, the above-described substituted or unsubstituted aralkyl group,the above-described substituted or unsubstituted arylalkenyl group, theabove-described substituted or unsubstituted arylthio group, theabove-described substituted or unsubstituted 5- or 6-memberedheterocyclic group with 1-3 nitrogen, oxygen, or sulfur atoms, or theabove-described substituted or unsubstituted 5- or 6-memberedheteroarylalkyl group; an acyloxy group containing the above-describedsubstituted or unsubstituted straight chain or branched C₁₋₁₀ alkylgroup, the above-described halo-C₁₋₄ lower alkyl group, theabove-described C₁₋₄ lower alkoxy group, the above-described C₁₋₄ loweralkylthio group, the above-described substituted or unsubstituted aminogroup, the above-described substituted or unsubstituted ureido group,the above-described substituted or unsubstituted C₃₋₁₀ cycloalkyl group,the above-described substituted or unsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀alkyl group, the above-described substituted or unsubstituted arylgroup, the above-described substituted or unsubstituted aralkyl group,the above-described substituted or unsubstituted arylalkenyl group, theabove-described substituted or unsubstituted arylthio group, theabove-described substituted or unsubstituted 5- or 6-memberedheterocyclic group with 1-3 nitrogen, oxygen, or sulfur atoms, or theabove-described substituted or unsubstituted 5- or 6-memberedheteroarylalkyl group; an aminocarbonyloxymethyl group that may besubstituted with the above-described substituted or unsubstitutedstraight chain or branched C₁₋₁₀ alkyl group, the above-describedhalo-C₁₋₄ alkyl group, the above-described C₁₋₄ lower alkoxy group, theabove-described C₁₋₄ lower alkylthio group, the above-describedsubstituted or unsubstituted C₃₋₁₀ cycloalkyl group, the above-describedsubstituted or unsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group, theabove-described substituted or unsubstituted aryl group, theabove-described substituted or unsubstituted aralkyl group, theabove-described substituted or unsubstituted arylalkenyl group, theabove-described substituted or unsubstituted 5- or 6-memberedheterocyclic group with 1-3 nitrogen, oxygen, or sulfur atoms, or theabove-described substituted or unsubstituted 5- or 6-memberedheteroarylalkyl group; a thiocarbonyl group containing theabove-described substituted or unsubstituted straight chain or branchedC₁₋₁₀ alkyl group, the above-described halo-C₁₋₄ lower alkyl group, theabove-described C₁₋₄ lower alkoxy group, the above-described C₁₋₄ loweralkylthio group, the above-described substituted or unsubstituted aminogroup, the above-described substituted or unsubstituted ureido group,the above-described substituted or unsubstituted C₁₋₁₀ cycloalkyl group,the above-described substituted or unsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀alkyl group, the above-described substituted or unsubstituted arylgroup, the above-described substituted or unsubstituted aralkyl group,the above-described substituted or unsubstituted arylalkenyl group, theabove-described substituted or unsubstituted arylthio group, theabove-described substituted or unsubstituted 5- or 6-memberedheterocyclic group with 1-3 nitrogen, oxygen, or sulfur atoms, or theabove-described substituted or unsubstituted 5- or 6-memberedheteroarylalkyl group; and a thio group containing the above-describedsubstituted or unsubstituted C₁₋₄ lower alkyl or aryl group.

[0410] More specifically, preferred as the “straight chain or branchedC₁₋₁₀ alkyl group” for R are methyl, ethyl, isopropyl, butyl, isobutyl,tert-butyl, heptyl, 1-propylbutyl, and 1-isobutyl-3-methylbutyl.

[0411] The “straight chain or branched C₂₋₁₀ alkenyl group” referred toas Rare preferably allyl, vinyl, isopropenyl, 1-methyl-2-propenyl,2-methyl-2-propenyl, 1-methyl-1-butenyl, crotyl, 1,3-dimethyl-2-butenyl,1-pentenyl, and 1-methyl-2-pentenyl.

[0412] The “halo-C₁₋₄ lower alkyl group” for R means a C₁₋₄ lower alkylgroup, particularly preferably a methyl group, substituted with theabove-described halogen atom, particularly preferably fluorine andchlorine, with being a trifluoromethyl group preferred.

[0413] The “substituted or unsubstituted C₃₋₁₀ cycloalkyl group” for Rmeans a C₃₋₁₀ cycloalkyl group (particularly preferably cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydroindenyl,decahydronaphthyl, adamantyl, andbicyclo[2.2.1]-heptyl)that may besubstituted with 1-4 substituents selected from the above-describedstraight chain or branched C₁₋₁₀ alkyl group, (particularly preferably aC₂₋₈ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, pentyl, isopentyl, 2,2-dimethylpropyl,4-methylpentyl, 2-ethylbutyl, or the like), the above-described straightchain or branched C₂₋₁₀ alkenyl group (particularly preferably a C₂₋₈alkenyl group such as 1-methylvinyl, 2-methylvinyl, 3-methyl-3-propenyl,or the like), the above-described C₃₋₁₀ cycloalkyl group (particularlypreferably a C₃₋₇ cycloalkyl group such as cyclopropyl, cyclopentyl,cyclohexyl, or the like), the above-described Cs. cycloalkenyl group(particularly preferably a C₅₋₆ cycloalkenyl group such ascyclopentenyl, cyclohexenyl, or the like), the above-described C₃₋₁₀cycloalkyl C₃₋₁₀ alkyl group (particularly preferably a C₃₋₇ cycloalkylC₁₋₄ alkyl group such as cyclopropylmethyl, 2-cyclopropylethyl,2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, or the like),the above-described aryl group (particularly preferably a phenyl group),an oxo group, the above described aralkyl group (particularly preferablya phenyl C₁₋₄ lower alkyl group such as benzyl, phenethyl, or the like),and the above-described arylalkenyl group (particularly preferably a2-phenylvinyl group). Preferable examples thereof include2,213,3-tetramethylcyclopropyl, 1-isopentylcyclobutyl,1-isopropylcyclopentyl, 1-isobutylcyclopentyl, 1-isopentylcyclopentyl,1-cyclohexylmethylcyclopentyl, cyclohexyl, 1-methylcyclohexyl,1-ethylcyclohexyl, 1-propylcyclohexyl, 1-isopropylcyclohexyl,1-butylcyclohexyl, 1-isobutylcyclohexyl, 1-pentylcyclohexyl,1-isopentylcyclohexyl, 1-(2,2-dimethylpropyl)-cyclohexyl,1-(4-methylpentyl)cyclohexyl, 1-(2-ethylbutyl) cyclohexyl,4-tert-butyl-1-isopentylcyclohexyl, 1-cyclopropylcyclohexyl,1-bicyclohexyl, 1-phenylcyclohexyl, 1-cyclopropylmethylcyclohexyl,1-cyclohexylmethylcyclohexyl, 1-(2-cyclopropylethyl) cyclohexyl,1-(2-cyclopentylethyl)cyclohexyl, 1-(2-cyclohexylethyl)cyclohexyl,4-methylcyclohexyl, 4-propylcyclohexyl, 4-isopropylcyclohexyl,4-tert-butylcyclohexyl, 4-pentylcyclohexyl, 4-bicyclohexyl,1-isopentylcycloheptyl, 3a-octahydroindenyl, 4a-decahydronaphthyl,1-adamantyl, and 7,7-dimethyl-1-(2-oxo)-bicyclo[2.2.1]heptyl. The siteof substitution is not specifically limited, but particularly preferablyat position 1. Any substitution group as described above may be used,but the straight chain or branched C₁₋₁₀ alkyl group is particularlypreferred.

[0414] The substituent for the “substituted or unsubstituted C₅.cycloalkenyl group” for R is the same as that for the above “substitutedor unsubstituted C₃₋₁₀ cycloalkyl group”. Specifically, it means acycloalkenyl group (especially cyclopentenyl and cyclohexenyl) that mayhave 1-4 substituents selected from the above-described straight chainor branched C₁₋₁₀ alkyl group (particularly preferably a C₁₋₈ alkylgroup such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,isopentyl, 2,2-dimethylpropyl, 4-methylpentyl, or the like), theabove-described straight chain or branched C₂₋₁₀ alkenyl group(particularly preferably a C₂₋₈ H alkenyl group such as 1-methylvinyl,2-methylvinyl, 3-methyl-3-propenyl, and the like), the above-describedC₃₋₁₀ cycloalkyl group (particularly preferably a C₃₋₇ cycloalkyl groupsuch as cyclopropyl, cyclopentyl, cyclohexyl, or the like), theabove-described C₅₋₈ cycloalkenyl group (particularly preferably a C₅₋₆cycloalkenyl group like cyclopentenyl, cyclohexenyl, or the like), theabove-described C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group (particularlypreferably a C₃₋₇ cycloalkyl C₁₋₄ lower alkyl group such as cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopentylethyl, cyclohexylmethyl,2-cyclohexylethyl, or the like), the above-described aryl group(particularly preferably a phenyl group), an oxo group, theabove-described aralkyl group (particularly preferably a phenyl C₁₋₄lower alkyl group such as benzyl, phenethyl, or the like), andarylalkenyl group (particularly preferably 2-phenylvinyl). Preferableexamples of the cycloalkenyl group includes 1-isopropyl-2-cyclopentenyl,1-isopropyl-3-cyclopentenyl, 1-isobutyl-2-cyclopentenyl,1-isobutyl-3-cyclopentenyl, 1-isopentyl-2-cyclopentenyl,1-isopentyl-3-cyclopentenyl, 1-cyclohexylmethyl-2-cyclopentenyl,1-cyclohexylmethyl-3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl,3-cyclohexenyl, 1-methyl-2-cyclohexenyl, 1-methyl-3-cyclohexenyl,1-ethyl-2-cyclohexenyl, 1-ethyl-3-cyclohexenyl, 1-propyl-2-cyclohexenyl,1-propyl-3-cyclohexenyl, 1-isopropyl-3-cyclohexenyl,1-butyl-2-cyclohexenyl, 1-butyl-3-cyclohexenyl,1-isobutyl-2-cyclohexenyl, 1-isobutyl-3-cyclohexenyl,1-pentyl-2-cyclohexenyl, 1-pentyl-3-cyclohexenyl, 1-iso pentyl-2-cyclohexenyl, 1-iso pentyl-3- cyclohexenyl,1-(2,2-dimethylpropyl)-2-cyclohexenyl,1-(2,2-dimethylpropyl)-3-cyclohexenyl,1-(4-methylpentyl)-2-cyclohexenyl, 1-(4-methylpentyl)-3-cyclohexenyl,1-cyclopropyl-2-cyclohexenyl, 1-cyclopropyl-3-cyclohexenyl,1-cyclohexyl-2-cyclohexenyl, 1-cyclohexyl-3-cyclohexenyl,1-phenyl-2-cyclohexenyl, 1-phenyl-3-cyclohexenyl,1-cyclopropylmethyl-2-cyclohexenyl, 1-cyclo propylmethyl-3-cyclohexenyl,1-cyclohexylmethyl-2-cyclohexenyl, 1-cyclohexylmethyl-3-cyclohexenyl,1-(2-cyclopropylethyl)-2-cyclohexenyl,1-(2-cyclopropylethyl)-3-cyclohexenyl,1-(2-cyclopentylethyl)-2-cyclohexenyl,1-(2-cyclopentylethyl)-3-cyclohexenyl,1-(2-cyclohexylethyl)-2-cyclohexenyl, and1-(2-cyclohexylethyl)-3-cyclohexenyl. There is no special restrictiononthe substitution position, but the particularly preferred position isposition 1. Any one of the above substituents may be used, but thestraight chain or branched C₁₋₁₀ alkyl group or the C₃₋₁₀ cycloalkylC₁₋₄ alkyl group is particularly preferred.

[0415] The “substituted or unsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀ alkylgroup” for R means a C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group (particularlypreferably cyclohexylmethyl, 1-cyclohexylethyl,1-cyclohexyl-1-methylethyl, 1-cyclohexyl-2-methylpropyl,1-cyclohexyl-3-methylbutyl, 1-cyclohexylhexyl,1-cyclohexyl-4-methylpentyl, and 1-cyclohexylheptyl) C₁₋₁₀ alkyl groupof which is straight chain or branched and which may have 1-4substituents selected from the above-described C₃₋₁₀ cycloalkyl group(particularly preferably a C₃₋₇ cycloalkyl group such as cyclopentyl orcyclohexyl), the above-described C₅₋₈ cycloalkenyl group (particularlypreferably a C,-7 cycloalkenyl group such as cyclopentenyl orcyclohexenyl), and the above-described aryl group (particularlypreferably a phenyl group). There is no special restriction on thesubstitution position. The above-described substituents may be placed atthe straight chain or branched C₁₋₁₀ alkyl moiety. Preferable examplesof the C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group include cyclohexylmethyl,1-cyclohexylethyl, cyclohexylcyclo-pentylmethyl, dicyclohexylmethyl,1-cyclohexyl-1-methylethyl, 1-cyclohexyl-2-methylpropyl,1-cyclohexyl-3-methylbutyl, 1-cyclohexyl-4-methylpentyl,1-cyclohexylhexyl, and 1-cyclohexylheptyl.

[0416] The “substituted or unsubstituted aryl group” for R means an arylgroup (particularly preferably a phenyl group) that may have 1-4substituents selected from the above-described straight chain orbranched C₁₋₆ alkyl group (particularly preferably a tert-butyl group),the above-described halogen atom (particularly preferably fluorine andchlorine), and a nitro group. Preferable examples of the aryl group arephenyl, 2-chlorophenyl, 4-nitrophenyl, and 3,5-di-tert-butylphenyl.

[0417] The “substituted or unsubstituted aralkyl” for R means an aralkylgroup (particularly preferably benzyl, benzhydryl, and trityl) which mayhave substituents selected from the above-described halogen atom(particularly preferably fluorine and chlorine), a nitro group, and ahydroxy group, and in which the C₁₋₄ lower alkyl group is straight chainor branched. There is no special restriction on the position ofsubstitution. The straight chain or branched C₁₋₄ lower alkyl moiety maybe substituted. Preferable examples of the aralkyl group are benzyl andtrityl.

[0418] The “substituted or unsubstituted 5- or 6-membered heterocyclicgroup having 1-3 nitrogen, oxygen or sulfur atoms” for R means theabove-described heterocyclic group that may have 1-4 substituentsselected from the above-described straight chain or branched C₁₋₆ alkylgroup (particularly preferably a tert-butyl group), the above-describedhalogen atom (particularly preferably fluorine and chlorine), and anitro group. The heterocyclic group is preferably an aromaticheterocyclic group, particularly preferably furyl, thienyl, and pyridyl.

[0419] The “substituted or unsubstituted straight chain or branchedC₁₋₁₀ alkyl group” for R, means a straight chain or branched C₁₋₁₀ alkylgroup that may have a substituent selected from the above-describedhalogen atom (particularly preferably fluorine and chlorine), theabove-described C₁₋₄ lower alkoxy group (particularly preferably amethoxy group), an amino group that may be substituted with theabove-described C₁₋₄ lower alkyl group (particularly preferably a methylgroup), the above-described acyl group (particularly preferably anacetyl group), or a hydroxyl group, the above-described C₁₋₄ loweralkylthio group (particularly preferably a methylthio group), acarbamoyl group, a hydroxyl group, an acyloxy group having theabove-described acyl group (particularly preferably an acetyloxy group),a carboxyl group, an acyl group (particularly preferably amethoxycarbonyl group), and an aryloxy group having the above-describedsubstituted or unsubstituted aryl group (particularly preferably aphenoxy group and a 4-chlorophenoxy group). Preferable examples of thealkyl group include methyl, chloromethyl, ethyl, isopropyl,1-methyl-2-pentyl, octyl, methoxymethyl, dimethylaminomethyl,acetylaminomethyl, 1-acetyl aminoethyl, 1-acetylamino-2-methylpropyl,1-acetylamino-3-methylbutyl, 1-acetylamino-3-methylthiopropyl,1-acetylamino-3-carbamoylpropyl, 1-hydroxy-1-methylethyl,1-acetyloxy-1-methylethyl, 4-carboxybutyl, 2-methoxycarbonylethyl,phenoxymethyl, and 4-chlorophenoxymethyl.

[0420] The “C₁₋₄ lower alkoxy group” for R₁ is preferably a methoxygroup and a tert-butoxy group.

[0421] The “C₁₋₄ lower alkylthio group” for R₁ is preferably amethylthio group.

[0422] The “substituted or unsubstituted amino group” for R₁ means anamino group that may have a substituent selected from theabove-described C₁₋₄ lower alkyl group (particularly preferably ethyl,isopropyl, and tert-butyl), the above-described acyl group (particularlypreferably acetyl and benzoyl), and the above-described aryl group(particularly preferably phenyl and 4-methoxyphenyl) that may besubstituted with the above-described C₁₋₄ lower alkoxy group. Preferableexamples of the amino group are ethylamino, isopropylamino,tert-butylamino, phenylamino, and 4-methoxyphenylamino.

[0423] The “substituted or unsubstituted ureido group” for R₁ means aureido group that may have a substituent selected from theabove-described C₁₋₄ lower alkyl group (particularly preferably methyland ethyl), the above-described acyl group (particularly preferablyacetyl and benzoyl), and the above-described aryl group (particularlypreferably phenyl and 4-methoxyphenyl) that may be substituted with theabove-described C₁₋₄ lower alkoxy group, with an N,N′-diphenylureidogroup being preferred.

[0424] The “substituted or unsubstituted C₃₋₁₀ cycloalkyl group” for R₁means a C₃₋₁₀ cycloalkyl group (particularly preferably cyclopropyl andcyclohexyl) that may have a substituent selected from theabove-described straight chain or branched C₁₋₁₀ alkyl group(particularly preferably methyl, tert-butyl, and isopentyl), an aminogroup, an amino group (particularly preferably methylamino, ethylamino,acetylamino, and benzylamino) that may be substituted with theabove-described C₁₋₄ lower alkyl or acyl groups. Preferable examples thecycloalkyl group are cyclopropyl, cyclohexyl, 1-methylcyclohexyl,1-isopentylcyclohexyl, 1-aminocyclohexyl, 1-acetylaminocyclohexyl, and4-tert-butylcyclohexyl.

[0425] The “substituted or unsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀ alkylgroup” for R₁ means a C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group which may havea substituent selected from the above-described C₃₋₁₀ cycloalkyl group(particularly preferably cyclopentyl and cyclohexyl), theabove-described C₅₋₈ cycloalkenyl group (particularly preferablycyclopentenyl and cyclohexenyl), and the above-described aryl group(particularly preferably a phenyl group) and in which the C₁₋₁₀ alkylmoiety is straight chain or branched. There is no special restriction onthe position of substitution. The straight chain or branched C₁₋₁₀ alkylmoiety may be substituted. A cyclohexylmethyl group is preferred as theC₁₋₁₀ cycloalkyl C₁₋₁₀ alkyl group.

[0426] The “substituted or unsubstituted aryl group” for R₁ means anaryl group (particularly preferably phenyl and naphthyl) that may have asubstituent selected from the above-described straight chain or branchedC₁₋₆ alkyl group (particularly preferably methyl and tert-butyl group),the above-described halogen atom (particularly preferably fluorine andchlorine), a nitro group, a hydroxyl group, the above-described C₁₋₄lower alkoxy group (particularly preferably a methoxy group), and theabove-described acyl group (particularly preferably a2-(1-isopentylcyclohexanecarbonylamino)phenylthiocarbonyl group).Preferable examples of the aryl group include phenyl, 1-naphthyl,2-naphthyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl,2-methoxyphenyl, 2-nitrophenyl, 4-nitrophenyl,3,5-di-tert-butyl-4-hydroxyphenyl, and4-[2-(1-isopentylcyclohexanecarbonylamino)phenylthiocarbonyl]phenyl.

[0427] The “substituted or unsubstituted aralkyl group” for R₁ means anaralkyl group (particularly preferably benzyl, phenethyl,3-phenylpropyl, naphthylmethyl, and biphenylmethyl) that may have asubstituent selected from the above-described halogen atom (particularlypreferably fluorine and chlorine), a nitro group, an amino group(particularly preferably amino, acetylamino, pivaloylamino,1-methylcyclohexanecarbonyl-amino, tert-butoxycarbonylamino, andbenzoylamino) that may be substituted with the above-described C₁₋₄lower alkyl group or the above-described acyl group, and a hydroxylgroup, and in which the C₁₋₄ lower alkyl group are straight chain orbranched. There is no special restriction on the position ofsubstitution. The straight chain or branched C₁₋₄ lower alkyl moiety maybe substituted. Preferable examples of the aralkyl group include benzyl,phenethyl, 3-phenylpropyl, 2-naphthylmethyl, 4-biphenylmethyl,benzhydryl, 2-chlorophenylmethyl, 3-chloro phenylmethyl,4-chlorophenylmethyl, 2-nitrophenylmethyl, 4-nitrophenylmethyl,2-pivaloylaminophenylmethyl,2-(1-methylcyclohexanecarbonylamino)phenylmethyl,2-tert-butoxy-carbonylaminophenylmethyl, 3-acetylaminophenylmethyl,3-(1-methylcyclohexanecarbonylamino)phenylmethyl, α-aminobenzyl,α-acetylaminobenzyl, α-(1-methylcyclohexanecarbonylamino)benzyl,-benzoylaminobenzyl, α-aminophenethyl, α-acetylaminophenethyl, and1-acetylamino-2-(4-hydorxyphenyl) ethyl.

[0428] The “substituted or unsubstituted arylalkenyl group” for R₁ meansan arylalkenyl group (particularly phenylvinyl) that may have asubstituent selected from the above-described straight chain or branchedC₁₋₆ lower alkyl group (particularly preferably methyl and tert-butyl),the above-described halogen atom (particularly preferably fluorine andchlorine), a nitro group, and a hydroxyl group, with a 2-phenylvinylgroup being preferred.

[0429] The “substituted or unsubstituted arylthio group” for R₁ means anarylthio group (particularly preferably a phenylthio group) that mayhave a substituent selected from the above-described halogen atom(particularly preferably fluorine and chlorine), a nitro group, and anamino group that may be substituted with the above-described C₁₋₄ loweralkyl group or the above-described acyl group (particularly preferablyamino, acetylamino, pivaloylamino, 1-methylcyclohexanecarbonylamino, andbenzoylamino), a hydroxyl group, and the above-described halo-C₁₋₄ loweralkyl group (particularly preferably a trifluoromethyl group).Preferably examples of the arylthio group include phenylthio,2-pivaloylaminophenylthio,2-(1-methylcyclohexanecarbonylamino)phenylthio, and 2-(1-methylcyclohexanecarbonylamino-4-trifluoromethyl)phenylthio.

[0430] The “substituted or unsubstituted 5- or 6-membered heterocyclicring groups with 1-3 nitrogen, oxygen, or sulfur atoms” for R₁ meansheterocyclic ring groups (particularly preferably an aromaticheterocyclic group such as pyridyl or a non-aromatic heterocyclic groupsuch as piperidyl or pyrrolidinyl) that may have substituents selectedfrom the above-described straight chain or branched C₁ alkyl group(particularly preferably a methyl group), a halogen atom (particularlypreferably fluorine and chlorine), the above-described acyl group(particularly preferably acetyl and benzoyl), and an oxo group.Preferable examples thereof are 3-pyridyl, 1-methyl-4-piperidyl,1-acetyl-4-piperidyl, 5-oxo-2-pyrrolidinyl, 1-acetyl-2-pyrrolidinyl, and1-benzoyl-2-pyrrolidinyl. A 4-piperidyl group such as1-methyl-4-piperidyl or 1-acetyl-4-piperidyl group is particularlypreferred.

[0431] The “substituted or unsubstituted 5- or 6-memberedheteroarylalkyl group” for R₁ means the above-described heteroarylalkylgroup (particularly preferably a 2-tenyl group) that may be substitutedwith the above-described straight chain or branched C₁₋₆ alkyl group(particularly preferably a methyl group) and the above-described halogenatom (particularly preferably fluorine and chlorine). A 2-tenyl group ispreferred.

[0432] The “substituted or unsubstituted C, ₄ lower alkyl group” for R₂means a C₁₋₄ lower alkyl group (particularly preferably a methyl group)that may have 1-3 substituents selected from the above-described C₁₋₄lower alkoxy group (particularly preferably a methoxy group), an aminogroup that may be substituted with the above-described C₁₋₄ lower alkylor acyl group (particularly preferably a dimethylamino group), theabove-described C₁₋₄ lower alkylthio group (particularly preferably amethylthio group), a carbamoyl group, a hydroxyl group, a carboxylgroup, the above-described acyl group (particularly preferably amethoxycarbonyl group), and the above-described heterocyclic group(particularly preferably an aromatic heterocyclic group such as thienylor a non-aromatic heterocyclic group such as tetrahydrofuryl). Atetrahydrofurylmethyl group is preferred.

[0433] The “substituted or unsubstituted aryl group” for R₂ is the sameas that for R₁. Preferable examples thereof are a phenyl group, ahalogenated phenyl group, an acylamino-substituted phenyl group, and thelike.

[0434] The “halogen atom” for X₁, X₂, X₃, and X₄ means a halogen atomincluding fluorine, chlorine, bromine, and the like, with fluorine andchlorine being preferred.

[0435] The “C₁₋₄ lower alkyl group” for X₁, X₂, X₃, and X₄ is preferablya methyl group.

[0436] The “halo-C₁₋₄ lower alkyl group” for X₁, X₂, X₃, and X₄ means aC₁₋₄ lower alkyl group (particularly preferably a methyl group)substituted with the above-described halogen atom (particularlypreferably fluorine and chlorine). A trifluoromethyl group is preferred.

[0437] The “C₁₋₄ lower alkoxy group” for X₁, X₂, X₃, and X₄,ispreferably a methoxy group.

[0438] The “acyl group” for X₁, X₂₁ X₃, and X₄ is preferably a benzoylgroup.

[0439] The “aryl group” for X₁, X₂, X₃, and X₄ is preferably a phenylgroup.

[0440] The “1-substituted-C₃₋₁₀ cycloalkyl group” for R″ means acycloalkyl group (forexample, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl, preferably a C₅₋₇ cycloalkyl group,particularly preferably a cyclohexyl group) that is substituted atposition 1 with substituents selected from the above-described straightchain or branched C₁₋₁₀ alkyl group (particularly preferably a C₁₋₈alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,pentyl, isopentyl, 2,2-dimethylpropyl, 4-methylpentyl, or 2-ethylbutyl),the above-described straight chain or branched C₂₋₁₀ alkenyl group(particularly preferably a C₂₋₈ alkenyl group such as 1-methylvinyl,2-methylvinyl, or 3-methyl-3-propenyl), the above-described C₃₋₁₀cycloalkyl (particularly preferably a C₃₋₇ cycloalkyl group such ascyclopropyl, cyclopentyl, or cyclohexyl), the above-described C₅₋₈cycloalkenyl group (particularly preferably a C., cycloalkenyl groupsuch as cyclopentenyl or cyclohexenyl), the above-described C₃₋₁₀cycloalkyl C₁₋₁₀ alkyl group (particularly preferably a C₃₋₇ cycloalkylC₁₋₄ lower alkyl group such as cyclopropylmethyl, 2-cyclopropylethyl,2-cyclopentylethyl, cyclohexylmethyl, or 2-cyclohexylethyl), theabove-described aryl group (particularly preferably a phenyl group), theabove-described aralkyl group (particularly preferably a phenyl C₁₋₄lower alkyl group such benzyl and phenethyl), and an arylalkenyl group(particularly preferably 2-phenylvinyl). Preferable examples of the1-substituted-C₃₋₁₀ cycloalkyl group include 1-isopentylcyclobutyl,1-isopropylcyclopentyl, 1-isobutylcyclopentyl, 1-isopentyl cyclopentyl,1-cyclohexylmethylcyclopentyl, 1-methylcyclohexyl, 1-ethylcyclohexyl,1-propylcyclohexyl, 1-isopropylcyclohexyl, 1-butylcyclohexyl,1-isobutylcyclohexyl, 1-pentylcyclohexyl, 1-isopentylcyclohexyl,1-(2,2-dimethylpropyl)cyclohexyl, 1-(4-methylpentyl)cyclohexyl,1-(2-ethylbutyl)cyclohexyl, 1-cyclopropylcyclohexyl, 1-bicyclohexyl,1-phenylcyclohexyl, 1-cyclopropylmethylcyclohexyl,1-cyclohexylmethylcyclohexyl, 1-(2-cyclopropylethyl)cyclohexyl,1-(2-cyclopentylethyl)cyclohexyl, 1-(2-cyclohexylethyl)cyclohexyl, and1-isopentylcycloheptyl. The straight chain or branched C₁₋₁₀ alkyl groupis particularly preferable as a substituent at position 1.

[0441] The “1-substituted-C₅₋₈ cycloalkenyl group” for R″ means acycloalkenyl groups (particularly preferably a C₅₋₆ cycloalkenyl groupsuch as cyclopentenyl or cyclohexenyl) that is substituted at position 1with substituents selected from the above-described straight chain orbranched C₁₋₁₀ alkyl group (particularly preferably a C₁alkyl group suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl,2,2-dimethyl propyl, and 4-methylpentyl), the above-described straightchain or branched C₂₋₁₀ alkenyl group (particularly preferably a C₂₋₈alkenyl group such as 1-methylvinyl, 2-methylvinyl, or3-methyl-3-propenyl), the above-described C₃₋₁₀ cycloalkyl group(particularly preferably a C₃₋₇ cycloalkyl group such as cyclopropyl,cyclopentyl, or cyclohexyl), the above-described C₅₋₈ cycloalkenyl group(particularly preferably a C₁₋₆ cycloalkenyl group such as cyclopentenylor cyclohexenyl), the above-described C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group(particularly preferably a C₃₋₇ cycloalkyl C₁₋₄ lower alkyl group suchas cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopentylethyl,cyclohexylmethyl, or 2-cyclohexylethyl), the above-described aryl group(particularly preferably a phenyl group), the above-described aralkylgroup (particularly preferably a phenyl C₁₋₄ lower alkyl group such asbenzyl or phenethyl), and the above-described arylalkenyl group(particularly preferably a 2-phenylvinyl group). Preferable examples ofthe 1-substituted-C₅₋₈ cycloalkenyl group include1-isopropyl-2-cyclopentenyl, 1-isopropyl-3-cyclopentenyl,1-isobutyl-2-cyclopentenyl, 1-isobutyl-3-cyclopentenyl,1-isopentyl-2-cyclopentenyl, 1-isopentyl-3-cyclopentenyl,1-cyclohexylmethyl-2-cyclopentenyl, 1-cyclohexylmethyl-3-cyclopentenyl,1-methyl-2-cyclohexenyl, 1-methyl-3-cyclohexenyl,1-ethyl-2-cyclohexenyl, 1-ethyl-3-cyclohexenyl, 1-propyl-2-cyclohexenyl,1-propyl-3-cyclohexenyl, 1-isopropyl-2-cyclohexenyl,1-isopropyl-3-cyclohexenyl, 1-butyl-2-cyclohexenyl,1-butyl-3-cyclohexenyl, 1-isobutyl-2-cyclohexenyl,1-isobutyl-3-cyclohexenyl, 1-pentyl-2-cyclohexenyl,1-pentyl-3-cyclohexenyl, 1-isopentyl-2-cyclohexenyl,1-isopentyl-3-cyclohexenyl, 1-(2,2-dimethylpropyl)-2-cyclohexenyl,1-(2,2-dimethylpropyl)-3-cyclohexenyl,1-(4-methylpentyl)-2-cyclohexenyl, 1-(4-methylpentyl)-3-cyclohexenyl,1-cyclopropyl-2-cyclohexenyl, 1-cyclopropyl-3-cyclohexenyl,1-cyclohexyl-2-cyclohexenyl, 1-cyclohexyl-3-cyclohexenyl,1-phenyl-2-cyclohexenyl, 1-phenyl-3-cyclohexenyl,1-cyclopropylmethyl-2-cyclohexenyl, 1-cyclopropylmethyl-3-cyclohexenyl,1-cyclohexylmethyl-2-cyclohexenyl, 1-cyclohexylmethyl-3-cyclohexenyl,1-(2-cyclopropylethyl)-2-cyclohexenyl,1-(2-cyclopropylethyl)-3-cyclohexenyl,1-(2-cyclopentylethyl)-2-cyclohexenyl,1-(2-cyclopentylethyl)-3-cyclohexenyl,1-(2-cyclohexylethyl)-2-cyclohexenyl, and1-(2-cyclohexylethyl)-3-cyclohexenyl. The straight chain or branchedC₁₋₁₀ alkyl group is particularly preferable as a substituent atposition 1.

[0442] The “prodrug compound” means the derivatives of compounds of thepresent invention having a chemically or metabolically degradable group,which exhibit pharmaceutical activity by degradation through hydrolysisor solvolysis, or under physiological conditions.

[0443] The “pharmaceutically acceptable salt” means any compound that isan atoxic salt formed with the compound represented by the above formula(I). Examples of such a salt include inorganic acid salts such ashydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates,phosphates, carbonates, bicarbonates, or perchlorates; organic acidsalts such as formates, acetates, trifluoroacetates, propionates,tartrates, glycolates, succinates, lactates, maleates, hydroxymaleates,methylmaleates, fumarates, adipiates, tartrates, malates, citrates,benzoates, cinnamates, ascorbates, salicylates, 2-acetoxybenzoates,nicotinates, or isonicotinates; sulfonates such as methane sulfonates,ethane sulfonates, isethionates, benzene sulfonates, p-toluenesulfonates, or naphthalene sulfonates; salts of acidic amino acids suchas aspargates or glutamates; alkali metal salts such as sodium salts orpotassium salts, alkaline earth metal salts such as magnesium salts orcalcium salts; ammonium salts; organic base salts such astrimethylamines, triethylamnes, pyridine salts, picoline salts,dicyclohexylamine salts or N,N′-dibenzyl ethylenediamine salts; andsalts of amino acids such as lysine salts or arginine salts. Dependingon the circumstances, hydrates or solvates with alcohols may be used.

[0444] More specifically, a 1-isobutylcyclohexyl group, a1-(2-ethylbutyl) cyclohexyl group, and a 1-isopentylcyclohexyl group areparticularly preferable as R in the formula (I), —CO— is particularlypreferable as Y, a hydrogen atom is particularly preferable as X₁, X₂,X₃, and X₄, and an isobutyryl group and a I-acetyl-4-piperidine carbonylgroup are particularly preferable as Z.

[0445] The compound of the present invention inhibits CETP activity andis expected as a conventionally unknown, new type of a preventive ortherapeutic agent for hyperlipidemia or atherosclerotic diseases.

[0446] When used as a pharmaceutical preparation, the compound of thepresent invention represented by the formula (I) or a pharmaceuticallyacceptable salt thereof can be usually used together with knownpharmacologically acceptable carriers, excipients, diluents, extenders,disintegrators, stabilizers, preservatives, buffers, emulsifiers,aromatics, colorants, sweeteners, viscosity increasing agents, flavorimproving agents, solubilizers, and other additives. More specifically,the compound can be formulated into dosage forms, such as tablets,pills, powders, granules, suppositories, injections, eye drops, liquiddrugs, capsules, troches, aerosols, elixirs, suspensions, emulsions, orsyrup, together with water, plant oil, alcohols such as ethanol orbenzyl alcohol, polyethylene glycol, glyceroltriacetate gelatin,lactose, carbohydrates such as starch, magnesium stearates, talc,lanolin, and vaseline, which can be administered orally or parenterally.

[0447] The above pharmaceutical preparations contain the compound of thepresent invention represented by the formula (I) or a pharmaceuticallyacceptable salt thereof in an amount effective to inhibit CETP activityand prevent or treat hyperlipidemia, atherosclerotic diseases, or thelike diseases attributable to CETP activity. One skilled in the art caneasily determine such an effective amount.

[0448] Doses may vary depending on the type and degree of diseases, thecompounds to be administered, the route of administration, the age, sex,and body weight of the patients. In the case of oral administration, itis usually desirable to administer the compound (I) to an adult 1-1000mg, particularly 50-800 mg per day.

[0449] The compound of the present invention can be produced using thefollowing method, but it is needless to say that the method of producingthe compound of the present invention is not limited to this method.

[0450] [Step 1]

[0451] The compound (II-2) (in the formula R, X₁, X₂, X₃, X₄, and Y areas described above) can be synthesized by reacting the compound (VI) (inthe formula X₁, X₂, X₃, and X₄ are as described above) with the compound(XII) (in the formula X represents a halogen atom and R and Y are asdescribed above) in the presence of a base such as pyridine,triethylamine, N-methylmorpholine, or N-methylpiperazine in an organicsolvent such as methylene chloride, chloroform, toluene, ether,tetrahydrofuran, dioxane, diisopropyl ether, dimethoxyethane, or hexane,water, or a mixture of these solvents, or in the absence of a solvent,under cooling through heating temperature.

[0452] The compound (III-2) can be synthesized from the compound (II-2)by the following step 2.

[0453] [Step 2]

[0454] The compound (III-2) (in the formula R, X₁, X₂, X₃, X₄, and Y areas described above) can be synthesized by allowing the compound (II-2)(in the formula R, X₁, X₂, X₃, X₄, and Y are as described above) toreact in the presence of a reducing agent such as sodium borohydride,lithium borohydride, aluminum lithium hydride, triphenylphosphine, zinc,or tin, in an organic solvent such as methanol, ethanol, ether, dioxane,tetrahydrofuran, diisopropyl ether, dimethoxyethane, toluene, hexane,acetone, or acetic acid, water, or a mixture of these solvents, undercooling through heating temperature.

[0455] The compound (II-2) or (IV-2) can also be synthesized from thecompound (III-2) using the following step 3 or 4.

[0456] [Step 3]

[0457] The compound (II-2) (in the formula R, X₁, X₂, X₃, X₄, and Y areas described above) can be synthesized by allowing the compound (III-2)(in the formula R, X₁, X₂, X₃, X₄, and Y are as described above) toreact in the presence of an oxidizing agent such as iodine, hydrogenperoxide, potassium permanganate, or dimethylsulfoxide, in an organicsolvent such as methanol, ethanol, ether, dioxane, tetrahydrofuran,diisopropyl ether, dimethoxyethane, acetone, toluene, hexane,dimethylformamide, or acetic acid, water, or a mixture of thesesolvents, or in the absence of a solvent, under cooling through heatingtemperature.

[0458] [Step 4]

[0459] The compound (IV-2) (in the formula R, R₁, X₁, X₂, X₃, X₄, Y, andY₁ are as described above) can be synthesized by reacting the compound(III-2) (in the formula R, X₁, X₂, X₃, X₄, and Y are as described above)with acid halide R₁—YX (in the formula R₁, X, and Y are as describedabove), isocyanate R₁—NY (in the formula R₁ and Y are as describedabove), carbonic halide R₁—O—YX (in the formula R₁, X, and Y are asdescribed above), or thiocarbonic halides R₁—S—YX (in the formula R₁, Xand Y are as described above) in the presence of a base such aspyridine, triethylamine, N-methylmorpholine, or N-methylbipiperazine, inan organic solvent such as methylene chloride, chloroform, toluene,ether, dioxane, tetrahydro furan, diisopropyl ether, dimethoxy ethane,or hexane, water, or a mixture of these solvents, or in the absence of asolvent, under cooling through heating temperature. Alternatively, thecompound (IV-2) can be synthesized by reacting the compound (III-2) withcarboxylic acid R₁—COOH (in the formula R₁ is as described above) orthiocarboxylic acid R₁—YSH (in the formula R₁ and Y are as describedabove) using a coupling agent such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,dicyclohexylcarbodiimide, diphenylphosphorylazide, orcarbonyldiimidazole, in the presence of an activating agent, ifrequired, such as 1-hydroxybenzotriazole, hydroxysuccinimide, orN-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, in an organicsolvent such as dimethylformamide, dichloromethane, chloroform,acetonitrile, tetrahydrofuran, dimethylsufoxide, carbon tetrachloride,or toluene, or a mixture of these solvents, under cooling throughheating temperature. (The reaction may be carried out in the presence ofa base such as pyridine or triethylamine.) Furthermore, the compound(IV-2) can be synthesized by reacting the compound (III-2) withcarboxylic acid R₁—COOH (in the formula R₁ is as described above) in thepresence of a base such as triethylamine or pyridine and in the presenceof ethyl chlorocarbonate or the like, in a organic solvent such as ethylacetate or tetrahydrofuran, or a mixture of these solvents, undercooling through heating temperature. When R₁ has a carboxyl group, thisabove step may be conducted using the corresponding ester to obtain thecompound by hydrolysis with acid using the known method.

[0460] The compound (IV-2) can also be synthesized by subsequentlyconducting the step 4 following the above step 2 or the step 7 below, orthe step 10 below, without isolating the compound (III-2).

[0461] The compound (V-2) can be synthesized by conducting the followingstep 5 or 5′. The step 5 is suitable especially when R₂ is the loweralkyl group that may have substituents and the step 5′ is suitableespecially when R₂ is the aryl group that may have substituents.

[0462] [Step 5]

[0463] The compound (V-2) (in the formula R, R₂, X₁, X₂, X₃, X₄,and Yare as described above) can be synthesized by allowing R₂—X (in theformula R₂ and X is as described above) and a sulfur compound likesodium thiosulfate to react in an organic solvent such as ethanol,methanol, tetrahydrofuran, dioxane, dimethoxyethane, acetone, oracetonitrile, water, or a mixture of these solvents, at room temperaturethrough heating temperature, and adding the compound (III-2) (in theformula R, X₁, X₂, X₃, X₄, and Y are as described above) and a basicaqueous solution such as sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, or sodium bicarbonate to the resultingsolution under ice-cooling through heating temperature.

[0464] [Step 5′]

[0465] The compound (V-2) (in the formula R, R₂, X₁, X₂, X₃, X₄, and Yare as described above) can be synthesized by reacting R₂—SH (in theformula R₂ is as described above) with trimethylsilane-imidazole incarbon tetrachloride under ice-cooling through room temperature, addingto the resulting solution a reaction mixture resulted from reacting thecompound (II-2) (in the formula R, X₁, X₂, X₃, X₄, and Y are asdescribed above) with sulfuryl chloride in carbon tetrachloride in thepresence of a base such as triethylamine, pyridine, N-methylmorpholine,or N-methylpiperazine under ice-cooling through room temperature, andallowing the resulting mixture to react.

[0466] The compound (III-2) can also be synthesized using the followingscheme.

[0467] [Step 6]

[0468] The compound (XI) (in the formula R, X₁, X₂, X₃, X₄, and Y are asdescribed above) can be synthesized by reacting the compound (X) (in theformula X₁, X₂, X₃, and X₄ are as described above) with the compound(XII) (in the formula R, X, and Y are as described above) in thepresence of a base such as pyridine, triethylamine, N-methylmorpholine,or N-methylpiperazine, in an organic solvent such as methylene chloride,chloroform, toluene, ether, dioxane, tetrahydrofuran, diisopropyl ether,dimethoxyethane, or hexane, water, or a mixture of these solvents, or inthe absence of a solvent, under cooling through heating temperature.

[0469] [Step 7]

[0470] The compound (III-2) (in the formula R, X₁, X₂, X₃, X₄, and Y areas described above) can be synthesized by allowing the compound (XI) (inthe formula R, X₁, X₂, X₃, X₄, and Y are as described above) to react inthe presence of a base such as sodium acetate, sodium hydroxide,potassium hydroxide, potassium carbonate, sodium carbonate, or sodiumbicarbonate, in an organic solvent such as methanol, ethanol,tetrahydrofuran, dioxane, dimethoxyethane, ether, or diisopropyl ether,water, or a mixture of these solvents, under ice-cooling through heatingtemperature.

[0471] The compound (III-2) can also be synthesized by the followingscheme.

[0472] [Step 8]

[0473] The compound (VIII) (in the formula R₁₁ and R₁₂ may be-the sameor different and are a lower alkyl group such as methyl or ethyl, andX₁, X₂, X₃, and X₄ are as described above) can be synthesized byreacting the compound (VII) (in the formula X₁, X₂, X₃, and X₄ are asdescribed above) with the compound (XIII) (in the formula R₁₁, R₁₂, andX are as described above) in the presence of a base such as sodiumhydride, triethylamine, or N-methylmorpholine, in an organic solventsuch as dimethylformamide, tetrahydrofuran, dioxane, or dimethoxyethaneor a mixture of these solvents, under cooling through heatingtemperature, and allowing the resulting product to react in an organicsolvent such as phenylether or sulfolane or a mixture of these solvents,or in the absence of a solvent, under heating.

[0474] [Step 9]

[0475] The compound (IX) (in the formula R, R₁₁, R₁₂, X₁, X₂, X₃, X₄,and Y are as described above) can be synthesized by allowing thecompound (VIII) (in the formula R₁₁, R₁₂, X₁, X₂, X₃, and X₄ are asdescribed above) to react in the presence of a reducing agent such asstannous chloride, zinc, iron, sodium dithionite, sodium sulfide, orsodium disulfide, in an organic solvent such as ethyl acetate, aceticacid, methanol, ethanol, tetrahydrofuran, dioxane, diisopropyl ether,dimethoxyethane, or toluene, water, or a mixture of these solvents,under cooling through heating temperature, and reacting the resultingproduct with the compound (XII) (in the formula R, X, and Y are asdescribed above) in the presence of a base such as pyridine,triethylamine, N-methylmorpholine, or N-methylpiperazine, in an organicsolvent such as chloroform, methylene chloride, tetrahydrofuran, ether,dioxane, dilsopropyl ether, dimethoxyethane, toluene, or hexane, wateror a mixture of these solvents, or in the absence of a solvent, undercooling through heating temperature.

[0476] [Step 10]

[0477] The compound (III-2) (in the formula R, X₁, X₂, X₃, X₄. and Y areas described above) can be synthesized by allowing the compound (IX) (inthe formula R, R₁₁, R₁₂, X₁, X₂, X₃, X₄, and Y are as described above)to react in the presence of a base such as potassium hydroxide, sodiumhydroxide, potassium carbonate, sodium carbonate, or sodium bicarbonate,in an organic solvent such as methanol, ethanol, tetrahydrofuran,dioxane, dimethoxyethane, ether, or diisopropyl ether, water, or amixture of these solvents, under cooling through heating temperature.

[0478] The compound (VI) can also be synthesized from the compound(VIII) by the following step 11.

[0479] [Step 11]

[0480] The compound (VI) (in the formula X₁, X₂, X₃, and X₄ are asdescribed above) can be synthesized by allowing the compound (VIII) (inthe formula R₁₁, R₁₂, X₁, X₂, X₃, and X₄ are as described above) toreact in the presence of a reducing agent such as stannous chloride,zinc, iron, sodium dithionite, sodium sulfide, and sodium disulfide, inan organic solvent such as ethyl acetate, acetic acid, methanol,ethanol, ether, tetrahydrofuran, dioxane, diisopropyl ether,dimethoxyethane, and toluene, water or a mixture of these solvents,under cooling through heating temperature, allowing the resultingproduct to react in the presence of a base such as potassium hydroxide,sodium hydroxide, potassium carbonate, sodium carbonate, or sodiumbicarbonate, in an organic solvents such as methanol, tetrahydrofuran,ethanol, dioxane, ether, diisopropyl ether, or dimethoxyethane, water,or a mixture of these solvents, under cooling through heatingtemperature, and allowing the product to react in the presence of anoxidizing agent such as iodine, hydrogen peroxide, potassiumpermanganate, or dimethylsufoxide, in an organic solvent such asmethanol, ethanol, ether, dioxane, tetrahydrofuran, diisopropyl ether,dimethoxyethane, acetone, toluene, hexane, dimethylformamide, or aceticacid, water, or a mixture of these solverrts, or in the absence of asolvent, under cooling through heating temperature.

[0481] The compound (I) thus obtained can be isolated and purified usingthe known method for separation and purification, such as concentration,concentration under reduced pressure, extraction, crystallization,recrystallization, or chromatography.

[0482] The compound of the present invention contains one or more ofstereoisomers due to the presence of the asymmetric carbon. Such isomersand mixtures thereof are all included in the scope of the presentinvention.

BEST MODE FOR CARRYING OUT THE INVENTION

[0483] In the following the present invention will be described indetail with reference to Examples and Test Example, but the presentinvention is not limited thereto.

EXAMPLE 1

[0484] Synthesis of bis-[2-(pivaloylamino)phenyl] disulfide (formula(I); R=t-butyl, X₁, X₂, X₃, X₄ =a hydrogen atom, Y=carbonyl,Z=2-(pivaloylamino)phenylthio)

[0485] Step 1) A mixture of bis-(2-aminophenyl) disulfide (8.00 g),pyridine (6.5 ml), and chloroform (150 ml) was stirred at 0° C., towhich pivaloyl chloride (83 ml) was added dropwise. After completion ofaddition, the organic layer was washed with water and saturated brine.After drying the organic layer over anhydrous sodium sulfate andevapolation, solid material was obtained. The solid thus obtained waswashed with ether-hexane and collected by filtration to give the desiredcompound (11.15 g, yield: 83%).

EXAMPLE 2

[0486] Synthesis ofbis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]-phenyl disulfide(formula (I); R=1-(2-ethylbutyl)cyclohexyl, X₁, X₂, X₃, X₄=a hydrogenatom, Y=carbonyl,Z=2-[1-(2-ethylbutyl)-cyclohexanecarbonylamino]phenylthio).

[0487] i) A suspension of 60% sodium hydride (980 mg) in tetrahydrofuran(80 ml) was stirred at room temperature and a tetrahydrofuran solution(10 ml) containing cyclohexanecarboxylic acid (3.00 g) was addeddropwise thereto. After completion of addition, a mixture was stirredfor 1 hour and cooled to 0° C., followed by adding a cyclohexanesolution (18.7 ml) containing 1.5 M lithium isopropylamide dropwisethereto. Then, after stirring at room temperature for 1.5 hours andcooling to 0° C., a tetrahydrofuran solution (10 ml) containing1-bromo-2-ethylbutane (4.64 g) was added dropwise thereto. The solutionwas gradually warmed to room temperature and stirred overnight. Waterand a 10% hydrochloride solution were added to this reaction solutionand the solution was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous sodium sulfate.After drying, the resulting solution was concentrated to obtain1-(2-ethylbutyl)cyclohexanecarboxylic acid (3.17 g, yield: 64%).

[0488] ii) A mixture of 1-(2-ethylbutyl)cyclohexane carboxylic acid(1.50 g) obtained in the above i), oxalyl chloride (0.85 ml), methylenechloride (20 ml), and a small amount of dimethylformamide was stirred atroom temperature for 1 hour, concentrated under reduced pressure toobtain 1-(2-ethylbutyl)cyclohexanecarbonyl chloride as a crude product.

[0489] Step 1) A pyridine solution (20 ml) containingbis-(2-aminophenyl) disulfide (825 mg) was stirred at room temperatureand a crude product of 1-(2-ethylbutyl)cyclohexanecarbonylchlorideobtained in the above ii) was added dropwise thereto. After completionof addition, the solution was stirred overnight at 100° C. Afterconcentration under reduced pressure, water was added to the reactionsolution and the solution was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous sodiumsulfate, followed by concentration. The resulting residue was purifiedby silica gel column chromatography (a developing solvent; hexane:ethylacetate=15:1) to obtain the desired compound (667 mg, yield: 32%).

EXAMPLES 3-8

[0490] The compounds shown in Tables 1 and 2 were obtained in the samemanner as in Examples 1 and 2. TABLE 1 Example Compound m.p. (° C.) ¹HNMR (CDCl₃ 300MHz) 1

86-87 8.52(2H, brs) 8.46(2H, dd, J=1.5, 8.4Hz) 7.40(2H, ddd, J=1.5, 7.8,8.4Hz) 7.21(2H, dd, J=1.5, 7.8Hz) 6.94(2H, dt, J=1.5, 7.8Hz) 1.25(18H,s) 2

Amorphous 8.58(2H, brs) 8.48(2H, dd, J=1.5, 8.4Hz) 7.42(2H, ddd, J=1.5,7.8, 8.4Hz) 7.13(2H, dd, J=1.5, 7.8Hz) 6.92(2H, dt, J=1.5, 7.8Hz)1.90-2.10(4H, m) 1.10-1.80(30H, m) 0.78(12H, t, J=7.2Hz) 3

144-145 8.93(2H, brs) 8.50(2H, dd, J=1.5, 8.4Hz) 7.69(4H, dd, J=1.5,8.4Hz) 7.40-7.60(8H, m) 7.31(2H, dt, J=1.5, 8.4Hz) 6.95(2H, dt, J=1.5,7.8Hz) 4

156-157 8.78(2H, brs) 8.40(2H, dd, J=1.5, 8.4Hz) 7.55(2H, dd, J=1.2,5.1Hz) 7.20-7.45(6H, m) 7.10(2H, dt, J=1.2, 5.1Hz) 6.95(2H, dt, J=1.5,7.8Hz) 5

157-158 8.44(2H, dd, J=1.5, 8.4Hz) 8.04(2H, brs) 7.41(2H, ddd, J=1.5,7.8, 8.4Hz) 7.24(2H, dd, J=1.5, 7.8Hz) 6.96(2H, dt, J=1.5, 7.8Hz)2.05-2.20(2H, m) 1.20-1.70(16H, m) 0.93(12H, t, J=7.2Hz) 6

Amorphous 8.51(2H, brs) 8.48(2H, dd, J=1.5, 8.4Hz) 7.40(2H, ddd, J=1.5,7.8, 8.4Hz) 7.22(2H, dd, J=1.5, 7.8Hz)- 6.95(2H, dt, J=1.5, 7.8Hz)1.80-2.00(4H, m) 1.25-1.70(16H, m) 1.18(6H, s)

[0491] TABLE 2 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300MHz) 7

Amorphous 8.46(2H, dd, J=1.5, 8.4Hz)8.41(2H, brs) 7.40(2H, ddd, J=1.5,7.8, 8.4Hz) 7.13(2H, dd, J=1.5, 7.8Hz) 6.91(2H, dt, J=1.5, 7.8Hz)2.00-2.15(4H, m) 1.45-1.75(18H, m) 1.15-1.25(4H, m) 0.87(12H, d,J=6.6Hz) 8

Amorphous 8.50(2H, brs) 8.49(2H, dd, J=1.5, 8.4Hz) 7.41(2H, ddd, J=1.5,7.8, 8.4Hz) 7.15(2H, dd, J=1.5, 7.8Hz) 6.92(2H, dt, J=1.5, 7.8Hz)1.89-2.00(4H, m) 1.10-1.66(26H, m) 0.85(12H, d, J=6.6Hz)

[0492] The compounds 1-1 through 1-19 shown in Tables 3 and 4 wereobtained in the same manner as in Examples 1 and 2. TABLE 3 No. Compound1-1

1-2

1-3

1-4

1-5

1-6

1-7

1-8

1-9

1-10

1-11

1-12

[0493] TABLE 4 No. Compound 1-13

1-14

1-15

1-16

1-17

1-18

1-19

Example 9

[0494] Synthesis of N-(2-mercaptophenyl)-2,2-dimethylpropioneamide(formula (I); R=t-butyl, X₁, X₂, X₃, X₄=a hydrogen atom, Y=carbonyl, Z=ahydrogen atom).

[0495] Step 2) A mixture of bis-[2-(pivaloylamino)phenyl] disulfide (300mg) obtained in Example 1 above in methanol (0.4 ml)-tetrahydrofuran (4ml) was stirred at room temperature. Sodium borohydride (70 mg) wasadded thereto and the resulting solution was refluxed under heating for4 hours. After cooling and addition of 10% hydrochloric acid, theresulting solution was extracted with ethyl acetate. The organic layerwas washed with water, and saturated brine, and was dried over anhydroussodium sulfate. After drying, the solution was concentrated and theresulting residue was separated and purified by silica gel columnchromatography (a developing solvent; hexane:ethyl acetate=10:1) toobtain the desired compound (84 mg, yield: 28%3.

EXAMPLE 10

[0496] Synthesis ofN-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide (formula(I); R=1-(2-ethylbutyl)cyclohexyl, X₁, X₂₁ X₃, X₄=a hydrogen atom,Y=carbonyl, Z=a hydrogen atom)

[0497] Step 2) A mixture ofbis-[2-[1-(2-ethylbutyl)cyclohexane-carbonylamino]phenyl] disulfide (667mg) obtained inExample2 above, triphenylphosphine (577 mg), dioxane (8ml), and water (4 ml) was stirred for 1 hour at 50° C. After allowingthe mixture to cool, a 1 N aqueous sodium hydroxide was added thereto.The aqueous layer was washed with hexane and neutralized with a 10%hydrochloride solution. After extraction with ethyl acetate, thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. After drying, the solution was concentrated and thethus-obtained residue was purified by silica gel column chromatography(a developing solvent; hexane:ethyl acetate=15:1), which resulted in thedesired compound (378 mg, yield: 56%). TABLE 5 Example Compound m.p. (°C.) ¹H NMR (CDCl₃ 300MHz) 9

69-71 8.42(1H, brs) 8.31(1H, dd, J=1.5, 8.4Hz) 7.50(1H, dd, J=1.5,7.8Hz) 7.30(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.08(1H, s) 1.36(9H, s) 10

68.5-74.0 8.45(1H, brs) 8.33(1H, dd, J=1.5, 8.4Hz) 7.51(1H, dd, J=1.5,7.8Hz) 7.31(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.07(1H, s) 2.05-2.25(2H, m) 1.20-1.80(15H, m) 0.79(6H, t, J=6.9Hz)

EXAMPLE 11

[0498] Synthesis ofN-(2-mercaptophenyl)-1-isopentylcyclohexane-carboxamide (formula (I);R=1-isopentylcyclohexyl, X₁, X₂, X₃, X₄=a hydrogen atom, Y=carbonyl, Z=ahydrogen atom).

[0499] Step 6)N-[2-(1-isopentylcyclohexane)carbonylthiophenyl]-1isopentylcyclohexanecarboxamide(formula (XI); R=1-isopentylcyclohexyl, X₁, X₂, X₃, X₄=a hydrogen atom,Y=carbonyl)

[0500] A pyridine solution (500 ml) containing 2-aminothiophenol (15.8g) was stirred at room temperature and 2 equal volumes of1-isopentylcyclohexanecarbonyl chloride was added dropwise thereto.After completion of addition, the solution was stirred for 2 hours at60° C. and allowed to cool. After removal of pyridine under reducedpressure, water was added and the solution was extracted with ethylacetate. The organic layer was washed with an aqueous solution ofsaturated sodium bicarbonate, hydrochloric acid, and saturated brine, inthis order, and dried over anhydrous sodium sulfate. The resultingsolution was concentrated under reduced pressure to give the desiredcompound in the form of a crude oily substance (60 g).

[0501] Step 7) The crude product obtained in the above step 6) (60 g)was dissolved in a mixed solvent of methanol (60 ml)-tetrahydrofuran (60ml) in the atmosphere of argon. Potassium hydroxide (24.2 g) was addedthereto and the solution was stirred for 1 hour at room temperature.After stirring, water (50 ml) was added, the solution was washed withhexane (50 ml×3), and the aqueous layer was acidified with potassiumhydrogen sulfate, followed by extraction with chloroform. The organiclayer was washed with water and saturated brine, dried over anhydroussodium sulfate, and the solvent was removed by evapolation under reducedpressure. The resulting deposited crystalline product was washed withpentane and collected by filtration to obtain the desired compound (23.1g, yield: 60%).

EXAMPLES 12-18

[0502] The compounds shown in Tables 6 and 7 were obtained in the samemanner as in Example 11. TABLE 6 Example Compound m.p. (° C.) ¹H NMR(CDCl₃ 300MHz) 11

109-110 8.34(1H, brs) 8.30(1H, dd, J=1.5, 8.4Hz) 7.50(1H, dd, J=1.5,7.8Hz) 7.31(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.01(1H, s) 1.10-2.20(15H, m) 0.85(6H, d, J=6.6Hz) 12

82-83 8.42(1H, brs) 8.31(1H, dd, J=1.5, 8.4Hz) 7.50(1H, dd, J=1.5,7.8Hz) 7.31(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.07(1H, s) 2.04-2.20(2H, m) 1.25-1.75(8H, m) 1.30(3H, s) 13

66-68 8.17(1H, dd, J=1.5, 8.4Hz) 8.26(1H, brs) 7.50(1H, dd, J=1.5,7.8Hz) 7.30(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.06(1H, s) 2.15-2.30(2H, m) 1.40-1.80(9H, m) 1.15(2H, m) 0.85(6H, d,J=6.6Hz) 14

120-121 8.37(1H, brs) 8.35(1H, dd, J=1.5, 8.4Hz) 7.50(1H, dd, J=1.5,7.8Hz) 7.31(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.07(1H, s) 2.12-2.20(2H, m) 1.15-1.83(9H, m) 0.97(6H, d, J=6.9Hz) 15

84-85 8.38(1H, brs) 8.32(1H, dd, J=1.5, 8.4Hz) 7.50(1H, dd, J=1.5,7.8Hz) 7.31(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.07(1H, s) 2.05-2.19(2H, m) 1.20-1.70(10H, m) 0.90(3H, t, J=7.2Hz) 16

93-94 8.38(1H, brs) 8.32(1H, dd, J=1.5, 8.4Hz) 7.50(1H, dd, J=1.5,7.8Hz) 7.30(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.07(1H, s) 2.05-2.20(2H, m) 1.20-1.70(12H, m) 0.88(3H, t, J=7.2Hz)

[0503] TABLE 7 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300MHz) 17

97-98 8.37(1H, brs) 8.31(1H, dd, J=1.5, 8.4Hz) 7.50(1H, dd, J=1.5,7.8Hz) 7.301H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.07(1H, s) 2.05-2.20(2H, m) 1.20-1.70(14H, m) 0.87(3H, t, J=7.2Hz) 18

92-93 8.42(1H, brs) 8.32(1H, dd, J=1.5, 8.4Hz) 7.51(1H, dd, J=1.5,7.8Hz) 7.31(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.00(1H, dt, J=1.5, 7.8Hz)3.07(1H, s) 2.06-2.20(2H, m) 1.20-1.95(11H, m) 0.89(6H, d, J=6.6Hz)

[0504] Further, the compounds 11-1 and 11-2 shown in Table 8 wereobtained in the same manner as in Example 11. TABLE 8 No. Compound 11-1

11-2

EXAMPLE 19

[0505] Synthesis ofN-(2-mercapto-5-methoxyphenyl)-1-methylcyclohexanecarboxamide (formula(I); R=1-methylcyclohexyl, X₁, X₃, X₄=a hydrogen atom, X₂=methoxy,Y=carbonyl, Z=a hydrogen atom

[0506] Step 8) S-(4-methoxy-2-nitrophenyl) N,N-dimethylthiocarbamate(formula (VIII); R₁₁, R₁₂=methyl, X₁, X₃, X₄=a hydrogen atom,X₂-methoxy).

[0507] A dimethylformamide solution (20 ml) containing4-methoxy-2-nitrophenol (4.00 g) was added dropwise to a suspension ofsodium hydride (1.04 g) in dimethylformamide (40 ml) at 0° C. understirring. After completion of addition, the mixture was stirred for 30minutes at room temperature, dimethylthiocarbamoyl chloride (3.65 g) wasfurther added thereto and the solution was stirred for 1 hour at 80° C.After allowing the solution to cool, water was added thereto and thesolution was extracted with ethyl acetate. The organic layer was washedwith 5% hydrochloric acid, water, and saturated brine, and was driedover anhydrous sodium sulfate. The solution was concentrated andether-hexane was added to the residue thus obtained. A deposited solidwas collected by filtration to obtain a yellow solid (5.11 g, yield:84%). Then, phenyl ether (10 ml) was added to the resulting product(3.50 g). After stirring for 1 hour at 210° C., the solution was allowedto cool. The resulting soflution was purified by silica gel columnchromatography (a developing solvent; hexane ethyl acetate=7: 1-3:2) toobtain the desired compound (3.35 g, yield: 96%).

[0508] Step 9) S-[2-(1-methylcyclohexanecarbonylamino)-4-methoxyphenyl)N,N-dimethylthiocarbamate (formula (IX); R=1-methylcyclohexyl, R₁₁,R₁₂=methyl, X₁, X₃, X₄=a hydrogen atom, X₃=methoxy, Y=carbonyl)

[0509] An ethyl acetate solution (75 ml) containing the compound (2.00g) obtained in the above step 8) and SnCl₂.2H₂O (3.65 g) was stirred atroom temperature overnight. Ethyl acetate (100 ml) was added to thesolution and, then, an aqueous sodium hydroxide was further addedthereto. Magnesium sulfate was added to the mixture and solid depositedwas filtered off. The filtrate was concentrated to obtainS-(2-amino-4-methoxyphenyl) N,N-dimethylthiocarbamate (1.64 g, yield:93%). After addition of pyridine (2.9 ml) and chloroform (20 ml)thereto, 1-methylcyclohexanecarbonyl chloride (1.39 g) was addeddropwise thereto at room temperature under stirring, followed bystirring for 1 hour. After distilling off the solvent, water was addedand the solution was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and was dried over anhydroussodium sulfate. The residue obtained by concentration was purified bysilica gel column chromatography (a developing solvent; hexane:ethylacetate=3:1) to obtain the desired compound (2.41 g, yield: 95%).

[0510] Step 10) The compound obtained in the above step 9) (250 mg) wasadded to a solution containing potassium hydroxide (140 mg) and methanol(1.5 ml)-tetrahydrofuran (0.5 ml), and the mixture was refluxed for 30minutes under heating. After allowing to cool, water was added and theaqueous layer was washed with hexane. The solution was acidified byadding an aqueous potassium hydrogensulfate, followed by extraction withethyl acetate. The organic layer was washed with water and a saturatedbrine, and was dried over anhydrous sodium sulfate. The residue obtainedafter concentration was purified by column chromatography (a developingsolvent; hexane:ethyl acetate=40:1) to obtain the desired compound (104mg, yield: 52%)

EXAMPLES 20-24

[0511] The compounds shown in Table 9 were obtained in the same manneras in Example 19. TABLE 9 Example Compound m.p. (° C.) ¹H NMR (CDCl₃300MHz) 19

Oil 8.75(1H, brs) 8.19(1H, dd, J=2.7Hz) 7.42(1H, d, J=8.4Hz) 6.57(1H,dd, J=2.7, 8.4Hz) 3.82(3H, s) 2.91(1H, s) 2.05-2.15(2H, m) 1.25-1.70(8H,m) 1.30(3H, s) 20

103-107 8.59(1H, s) 8.34(1H, brs) 7.61(1H, s) 3.10(1H, s) 2.00-2.20(2H,m) 1.10-1.75(13H, m) 0.86(6H, d, J=6.6Hz) 21

56-57 8.75(1H, s) 8.55(1H, brs) 7.60(1H, s) 3.09(1H, s) 1.10-2.20(13H,m) 0.87(6H, d, J=6.6Hz) 22

83.5-85.5 8.44(1H, brs) 8.22(1H, d, J=1.5Hz) 7.33(1H, d, J=7.8Hz)6.83(1H, dd, J=1.5, 7.8Hz) 2.96(1H, s) 2.34(3H, s) 1.10-2.20(15H, m)0.85(6H, d, J=6.6Hz) 23

85-87 8.50(1H, brs) 8.17(1H, dd, J=1.5, 8.4Hz) 7.21(1H, t, J=8.4Hz)7.00(1H, dd, J=1.5, 8.4Hz) 2.73(1H, brs) 2.47(3H, s) 2.05-2.20(2H, m)1.10-1.75(13H, m) 0.86(6H, d, J=6.6Hz) 24

71-72 8.20(1H, brs) 8.12(1H, d, J=8.4Hz) 7.31(1H, s,) 7.10(1H, d,J=8.4Hz) 3.05(1H, s) 2.28(3H, s) 2.08-2.16(2H, m) 1.13-1.60(13H, m)0.85(6H, d, J=6.6Hz)

[0512] The compounds 19-1 through 19-9 shown in Table 10 were alsoobtained in the same manner as in Example 19. TABLE 10 No. Compound 19-1

19-2

19-3

19-4

19-5

19-6

19-7

19-8

19-9

EXAMPLE 25

[0513] Synthesis of S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thioacetate (formula (I); R=l-isopentylcyclohexyl, X₁, X₂, X₃, X₄=ahydrogen atom, Y=carbonyl, Z=acetyl)

[0514] Step 4) Acetyl chloride (0.17 ml) was added dropwise to achloroform solution (10 ml) containingN-(2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide (600 mg) obtainedin the same manner as in step 2) of Example 9, step 7) of Example 11, orthe step 10) of Example 19 and pyridine (0.48 ml) at room temperatureunder stirring. The solution was stirred for 1 hour. The residueobtained after concentration was purified by silica gel columnchromatography (a developing solvent hexane:ethyl acetate=12:1) toobtain the desired compound (666 mg, yield: 98%).

EXAMPLE 26

[0515] Synthesis ofS-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]-phenyl]2-methylthiopropionate (formula (I); R=1-(2-ethylbutyl)cyclohexyl, X₁,X₂, X₃, X₄=a hydrogen atom, Y=carbonyl, Z=isobutyryl)

[0516] Step 4) Isobutyryl chloride (15.0 ml) was added dropwise to achloroform solution (300 ml) containingN-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide (43.72 g)obtained in Example 10 and pyridine (27.7 ml) at room temperature understirring. The solution was stirred for 1 hour. After concentration,hexane was added and the deposited solid was filtered off. The filtratewas concentrated and the resulting residue was purified by silica gelcolumn chromatography (a developing solvent; hexane:ethyl acetate=15:1)to obtain the desired compound (50.72 g, yield: 95%).

EXAMPLE 27

[0517] Synthesis of S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate (formula (I); R=l-isobutylcyclohexyl, X₁, X₂, X₃,X₄=a hydrogen atom, Y=carbonyl, Z=isobutyryl)

[0518] Step 4) Isobutyryl chloride (0.92 ml) was added dropwise to achloroform solution (25 ml) containingN-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide (2.50 g) obtainedin Example 18 and pyridine (1.8 ml) at room temperature under stirring.The solution was stirred for 1 hour. The residue obtained afterconcentration was purified by silica gel column chromatography (adeveloping solvent; hexane:ethyl acetate=15:1) to obtain the desiredcompound (2.94 g, yield: 95%).

EXAMPLE 2

[0519] Synthesis ofS-(2-(1-(2-ethylbutyl)cyclohexanecarbonylamino)-phenyl]1-acetylpiperidine-4-thiocarboxylate (formula (I);R=1-(2-ethylbutyl)cyclohexyl, X₁, X₂, X₃, X,=a hydrogen atom,Y=carbonyl, z=1-acetyl-4-piperidinecarbonyl)

[0520] Step 4) A chloroform solution (10 ml) containingN-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide (933 mg)obtained in Example 10 and pyridine (0.5 ml)was added dropwise to achloroform solution (10 ml) containing 1-acetylisonipecotic acid (500mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (616mg), and 1-hydroxybenzotriazole (435 mg) at room temperature. Thesolution was stirred for 1 hour. After stirring, water was added and thesolution was extracted with ethyl acetate. The organic layer was washedwith a saturated brine and dried over anhydrous sodium sulfate. Theresidue obtained after concentration was purified by silica gel columnchromatography (a developing solvent; hexane ethylacetate=4:1-chloroform:methanol=10:1) to obtain the desired compound(1.08 g, yield: 79%).

EXAMPLE 28,

[0521] The compound of Example 28 (formula (I);R=1-(2-ethylbutyl)-cyclohexyl, X₁, X₂, X₃, X₄=a hydrogen atom,Y=carbonyl, Z=1-acetyl-4-piperidinecarbonyl) was synthesized usinganother synthesis method.

[0522] Step 4) Triethylamine (541 ml) was added to an ethylacetatesuspension (2 liters) containing 1-acetylisonipecotic acid (331 g) undera stream of argon. The solution was stirred under ice cooling. An ethylacetate solution (400 ml) containing ethyl chlorocarbonate (185 ml) wasadded dropwise thereto and the mixture was further stirred for 100 minunder spontaneous elevation of the temperature. After ice-cooling, anethyl acetate solution (2 liters) ofN-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide (618 g)obtained in Example 10 was added dropwise to the reaction solution,which was stirred further for 15 minutes under ice-cooling. Afterstirring, 1 N hydrochloric acid (1.3 liter) was added, the organic layerwas washed successively with water, an aqueous saturated sodiumbicarbonate, water, and a saturated brine, and dried over anhydroussodium sulfate. The residue obtained after concentration was dissolvedin diisopropyl ether (2.5 liter) and the solution was stirred forcrystallization to obtain a crude crystal. The crystal was furtherdissolved in diisopropyl ether (5.5 liter) under heating and thesolution was stirred for crystallization to obtain the desired compound(505 g, yield:55%).

EXAMPLE 29-65

[0523] The compounds shown in Tables 11-17 were obtained in the samemanner as in Examples 25, 26, 27, 28, or 28′. TABLE 11 Example Compoundm.p. (° C.) ¹H NMR (CDCl₃ 300MHz) 25

54-55 8.34(1H, dd, J=1.5, 8.4Hz) 8.05(1H, brs) 7.46(1H, ddd, J=1.5, 7.8,8.4Hz) 7.39(1H, dd, J=1.5, 7.8Hz) 7.12(1H, dt, J=1.5, 7.8Hz) 2.45(3H, s)2.03(2H, m) 1.10-1.61(13H, m) 0.85(6H, d, J=6.6Hz) 26

63.0-63.5 8.40(1H, dd, J=1.5, 8.4Hz) 8.12(1H, brs) 7.45(1H, ddd, J=1.5,7.8, 8.4Hz) 7.38(1H, dd, J=1.5, 7.8Hz) 7.11(1H, dt, J=1.5, 7.8Hz)2.94(2H, sept, J=6.9Hz) 1.95-2.20(2H, m) 1.15-1.75(15H, m) 1.30(6H, d,J=6.9Hz) 0.78(6H, t, J=6.9Hz) 27

63.5-65.5 8.39(1H, dd, J=1.5, 8.4Hz) 8.10(1H, brs) 7.45(1H, ddd, J=1.5,7.8, 8.4Hz) 7.38(1H, dd, J=1.5, 7.8Hz) 7.11(1H, dt, J=1.5, 7.8Hz)2.94(2H, sept, J=6.9Hz) 1.95-2.10(2H, m) 1.10-1.85(11H, m) 1.29(6H, d,J=6.9Hz) 0.87(6H, d, 3=6.6Hz) 28

89.0-91.5 8.37(1H, dd, J=1.5, 8.4Hz) 8.03(1H, brs) 7.46(1H, ddd, J=1.5,7.8, 8.4Hz) 7.36(1H, dd, J=1.5, 7.8Hz) 7.11(1H, dt, J=1.5, 7.8Hz)4.58(1H, m) 3.88(1H, m) 3.18(1H, m) 2.91(1H, m) 2.82(1H, m)1.95-2.20(4H, m) 2.11(3H, s) 1.15-1.85(17H, m) 0.78(6H, t, J=6.9Hz) 29

144-145 8.52(1H, brs) 8.42(1H, dd, J=1.5, 8.1Hz) 8.34(2H, dd, J=1.8,6.9Hz) 8.00(2H, dd, J=1.8, 6.9Hz) 7.54(1H, ddd, J=1.5, 7.5, 8:1Hz)7.45(1H, dd, J=1.5, 7.5Hz) 7.23(1H, dt, J=1.5, 7.5Hz) 1.34(9H, s) 30

41-42 8.39(1H, dd, J=1.5, 8.4Hz) 8.07(1H, brs) 7.44(1H, ddd, J=1.5, 7.8,8.4Hz) 7.36(1H, dd, J=1.5, 7.8Hz) 7.10(1H, dt, J=1.5, 7.8Hz)1.96-2.05(2H, m) 1.15-1.65(8H, m) 1.35(9H, s) 1.22(3H, s)

[0524] TABLE 12 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300MHz) 31

61-62 8.32(1H, dd, J=1.5, 8.4Hz) 7.85(1H, brs) 7.20-7.50(7H, m) 7.10(1H,dt, J=1.5, 7.8Hz) 3.94(2H, s) 1.17(9H, s) 32

78.5-79.0 8.40(1H, dd, J=1.5, 8.4Hz) 8.17(1H, brs) 8.05(2H, m) 7.66(1H,ddd, J=1.5, 7.8, 8.4Hz) 7.43-7.60(4H, m) 7.17(1H, dt, J=1.5, 7.8Hz)1.85-2.00(2H, m) 1.10-1.70(8H, m) 1.18(3H, s) 33

55-56 8.39(1H, dd, J=1.5, 8.4Hz) 8.04(1H, brs) 7.45(1H, ddd, J=1.5, 7.8,8.4Hz) 7.36(1H, dd, J=1.5, 7.8Hz) 7.10(1H, dt, J=1.5, 7.8Hz)2.00-2.03(2H, m) 1.10-1.60(13H, m) 1.35(9H, s) 0.85(6H, d, J=6.6Hz) 34

155-156 8.39(1H, dd, J=1.5, 8.4Hz) 7.98(1H, brs) 7.47(1H, ddd, J=1.5,7.8, 8.4Hz) 7.09-7.38(7H, m) 5.85(1H, d, J=7.8Hz) 5.04(1H, dt, J=5.7,7.8Hz) 3.20(1H, dd, J=6.0, 14.1Hz) 3.11(1H, dd, J=7.5, 14.1Hz)1.97-2.10(5H, m) 1.00-1.80(13H, m) 0.81(6H, d, J=6.6Hz) 35

106-110 9.42(1H, s) 9.14(1H, d, J=5.1Hz) 8.90(1H, d, J=8.1Hz) 8.32(1H,d, J=7.8Hz) 8.12(1H, m) 7.89(1H, s) 7.58(1H, t, J=7.8Hz) 7.49(1H, d,J=7.8Hz) 7.24(1H, t, J=7.8Hz) 5.94(1H, brs) 1.89-2.03(2H, m)1.07-1.60(13H, m) 0.80(6H, d, J=6.6Hz) 36

68-69 8.35(1H, dd, J=1.5, 8.4Hz) 7.93(1H, brs) 7.50(1H, ddd, J=1.5, 7.8,8.4Hz) 7.40(1H, dd, J=1.5, 7.8Hz) 7.15(1H, dt, J=1.5, 7.8Hz) 4.28(2H, s)1.96-2.09(2H, m) 1.09-1.65(13H, m) 0.85(6H, d, J=6.6Hz)

[0525] TABLE 13 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300MHz) 37

53-54 8.37(1H, dd, J=1.5, 8.4Hz) 7.98(1H, brs) 7.47(1H, ddd, J=1.5, 7.8,8.4Hz) 7.39(1H, dd, J=1.5, 7.8Hz) 7.13(1H, dt, J=1.5, 7.8Hz) 4.19(2H, s)3.58(3H, s) 1.95-2.10(2H, m) 1.05-1.65(13H, m) 0.84(6H, d, J=6.6Hz) 38

40-41 8.35(1H, dd, J=1.5, 8.4Hz) 8.06(1H, brs) 7.45(1H, ddd, J=1.5, 7.8.8.4Hz) 7.39(1H, dd, J=1.5, 7.8Hz) 7.17(1H, dt, J=1.5, 7.8Hz) 2.72(2H, q,J=7.5Hz) 1.95-2.10(2H, m) 1.10-1.60(13H, m) 1.24(3H, t, J=7.2Hz)0.85(6H, d, J=6.6Hz) 39

60.5-62.0 8.37(1H, dd, J=1.5, 8.4Hz) 7.90(1H, brs) 6.90-7.50(8H, m)4.79(2H, s) 1.00-2.00(15, m) 0.83(6H, d, J=6.6Hz) 40

51-52 8.30(1H, dd, J=1.5, 8.4Hz) 8.00(1H, brs) 7.40(1H, ddd, J=1.5, 7.8,8.4Hz) 7.33(1H, dd, J=1.5, 7.8Hz) 7.06(1H, dt, J=1.5, 7.8Hz) 2.88(1H, m)1.94-1.98(2H, m) 1.07-1.51(13H, m) 1.24(6H, d, J=7.0Hz) 0.85(6H, d,J=6.6Hz) 41

95-96 8.35(1H, dd, J=1.5, 8.4Hz) 7.87(1H, brs) 7.48(1H, ddd, J=1.5, 7.8,8.4Hz) 7.37(1H, dd, J=1.5, 7.8Hz) 7.31(2H, m) 7.14(1H, dt, J=1.5, 7.8Hz)6.93(2H, m) 4.78(2H, s) 1.90-1.94(2H, m) 1.07-1.58(13H, m) 0.83(6H, d,J=6.6Hz) 42

52-53 8.31(1H, dd, J=1.5, 8.4Hz) 8.09(1H, brs) 7.45(1H, ddd, J=1.5, 7.8,8.4Hz) 7.41(1H, dd, J=1.5, 7.8Hz) 7.10(1H, dt, J=1.5, 7.8Hz)1.92-2.25(3H, m) 1.00-1.75(17H, m) 0.86(6H, d, J=6.6Hz)

[0526] TABLE 14 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300MHz) 43

Oil 8.36(1H, dd, J=1.5, 8.4Hz) 8.05(1H, brs) 7.44(1H, ddd, J=1.5, 7.8,8.4Hz) 7.37(1H, dd, J=1.5, 7.8Hz) 7.12(1H, dt, J=1.5, 7.8Hz)2.55-2.75(1H, m) 1.95-2.10(4H, m) 1.10-1.85(21H, m) 0.85(6H, d, J=6.6Hz)44

Amorphous 8.38(1H, d, J=8.7Hz) 8.15(1H, brs) 8.04-8.08(2H, m) 7.66(1H,m) 7.48-7.55(4H, m) 7.16(1H, dt, J=1.2, 7.8Hz) 1.93-2.14(2H, m)1.07-1.51(13H, m) 0.78(6H, d, J=6.6Hz) 45

136-138 8.41(1H, dd, J=1.5, 8.4Hz) 8.01(1H, brs) 7.46(1H, ddd, J=1.5.7.8, 8.4Hz) 7.34(1H, dd, J=1.5, 7.8Hz) 7.23(1H, d, J=7.1Hz) 7.11(1H, dt,J=1.5, 7.8Hz) 5.72(1H, brs) 5.41(1H, brs) 4.69(1H, m) 1.95-2.58(6H, m)1.05-1.70(13H, m) 0.85(6H, d, J=6.6Hz) 46

91-92 8.42(1H, dd, J=1.5, 8.4Hz) 7.99(1H, brs) 7.47(1H, ddd, J=1.5, 7.8,8.4Hz) 7.37(1H, dd, J=1.5, 7.8Hz) 7.12(1H, dt, J=1.5, 7.8Hz) 2.64(1H,brs) 1.90-2.10(2H, m) 1.05-1.70(13H, m) 1.54(6H, s) 0.86(6H, d, J=6.6Hz)47

144-146 9.90(3H, brs) 8.07(1H, dd, J=1.5, 8.4Hz) 7.98(1H, s) 7.42(1H,ddd, J=1.5, 7.8, 8.4Hz) 7.41(1H, dd, J=1.5, 7.8Hz) 7.10(1H, dt, J=1.5,7.8Hz) 1.95-2.20(2H, m) 1.10-1.85(21H, m) 0.84(6H, d, J=6.6Hz) 48

45-46 8.37(1H, dd, J=1.5, 8.4Hz) 7.93(1H, brs) 7.43(1H, ddd, J=1.5, 7.8,8.4Hz) 7.35(1H, dd, J=1.5, 7.8Hz) 7.09(1H, dt, J=1.5, 7.8Hz)2.05-2.20(2H, m) 1.45-1.75(9H, m) 1.36(9H, s) 1.10-1.25(2H, m) 0.86(6H,d, J=6.6Hz)

[0527] TABLE 15 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300MHz) 49

50-51 8.33(1H, dd, J=1.5, 8.4Hz) 7.95(1H, brs) 7.46(1H, ddd, J=1.5, 7.8,8.4Hz) 7.40(1H, dd, J=1.5, 7.8Hz) 7.12(1H, dt, J=1.5, 7.8Hz) 2.46(3H, s)2.05-2.25(2H, m) 1.40-1.80(9H, m) 1.10-1.25(2H, m) 0.87(6H, d, J=6.6Hz)50

129-130 8.72(1H, s) 8.01(1H, brs) 7.44(1H, s) 1.90-2.10(2H, m)1.10-1.75(13H, m) 1.35(9H, s) 0.85(6H, d, J=6.6Hz) 51

66-67 8.68(1H, s) 7.88(1H, brs) 7.43(1H, s) 2.05-2.20(2H, m)1.30-1.75(9H, m) 1.35(9H, s) 1.05-1.20(2H, m) 0.86(6H, d, J=6.6Hz) 52

69-71 8.82(1H, d, J=1.5Hz) 8.16(1H, brs) 7.48(1H, d, J=8.1Hz) 7.34(1H,dd, J=1.5, 8.1Hz) 1.90-2.15(2H, m) 1.05-1.75(13H, m) 1.37(9H, s)0.86(6H, d, J=6.6Hz) 53

Oil 8.35(1H, dd, J=1.5, 8.4Hz) 8.05(1H, brs) 7.47(1H, ddd, J=1.5, 7.8,8.4Hz) 7.39(1H, dd, J=1.5, 7.8Hz) 7.13(1H, dt, J=1.5, 7.8Hz) 2.74(2H, t,J=6.9Hz) 2.40(2H, t, J=6.9Hz) 1.90-2.10(2H, m) 1.05-1.90(17H, m)0.86(6H, d, J=6.6Hz) 54

Oil 8.39(1H, dd, J=1.5, 8.4Hz) 8.27(1H, brs) 7.52(1H, dd, J=1.5, 7.8Hz)7.47(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.11(1H, dt, J=1.5, 7.8Hz) 3.84(3H, s)2.00-2.10(2H, m) 1.10-1.65(13H, m) 0.85(6H, d, J=6.6Hz)

[0528] TABLE 16 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300MHz) 55

Oil 8.44(1H, dd, J=1.5, 8.4Hz) 8.29(1H, brs) 7.35-7.55(7H, m) 7.13(1H,dt, J=1.5, 7.8Hz) 1.95-2.15(2H, m) 1.25-1.70(8H, m) 1.27(3H, s) 56

40-41 8.58(1H, brs) 8.42(1H, dd, J=1.5, 7.7Hz) 7.61(1H, dd, J=1.5,7.7Hz) 7.53(1H, dt, J=1.5, 7.7Hz) 7.10-7.35(7H, m) 2.03-2.09(2H, m)1.09-1.59(13H, m) 0.78(6H, d, J=6.6Hz) 57

103 8.80(1H, d, J=1.5Hz) 8.16(1H, brs) 7.48(1H, d, J=8.1Hz) 7.35(1H, dd,J=1.5, 7.8Hz) 1.37(9H, s) 1.30(9H, s) 58

Oil 8.22(1H, d, J=1.5Hz) 8.03(1H, brs) 7.26(1H, d, J=7.8Hz) 6.93(1H, dd,J=1.5, 7.8Hz) 2.43(3H, s) 2.38(3H, s) 1.10-2.10(15H, m) 0.85(6H, d,J=6.6Hz) 59

76.5-79.0 8.38(1H, dd, J=1.5, 8.4Hz) 8.13(1H, brs) 7.47(1H, ddd, J=1.5,7.8, 8.4Hz) 7.40(1H, dd, J=1.5, 7.8Hz) 7.12(1H, dt, J=1.5, 7.8Hz)2.46(3H, s) 2.00-2.15(2H, m) 1.15-1.70(15H, m) 0.79(6H, t, J=6.9Hz) 60

64.5-66.5 8.42(1H, dd, J=1.5, 8.4Hz) 8.11(1H, brs) 7.45(1H, ddd, J=1.5,7.8, 8.4Hz) 7.36(1H, dd, J=1.5, 7.8Hz) 7.10(1H, dt, J=1.5, 7.8Hz)1.95-2.15(2H, m) 1.10-1.75(15H, m) 1.36(9H, s) 0.79(6H, t, J=6.9Hz)

[0529] TABLE 17 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300MHz) 61

67.5-69.5 8.40(1H, dd, J=1.5, 8.4Hz) 8.06(1H, brs) 7.47(1H, ddd, J=1.5,7.8, 8.4Hz) 7.39(1H, dd, J=1.5, 7.8Hz) 7.13(1H, dt, J=1.5, 7.8Hz)4.20(2H, s) 3.59(3H, s) 1.95-2.15(2H, m) 1.10-1.75(15H, m) 0.79(6H, t,J=6.9Hz) 62

68.0-70.0 8.44(1H, dd, 1.5, 8.4Hz) 8.06(1H, brs) 7.47(1H, ddd, J=1.5,7.8, 8.4Hz) 7.37(1H, dd, J=1.5, 7.8Hz) 7.12(1H, dt, J=1.5, 7.8Hz)2.61(1H, s) 2.00-2.15(2H, m) 1.15-1.75(15H, m) 1.54(6H, s) 0.78(6H, t,J=6.9Hz) 63

62.0-63.0 8.39(1H, dd, J=1.5, 8.4Hz) 7.95(1H, brs) 7.48(1H, ddd, J=1.5,7.8, 8.4Hz) 7.38(1H, dd, J=1.5, 7.8Hz) 7.32(2H, m) 7.14(1H, dt, J=1.5,7.8Hz) 6.94(2H, m) 4.78(2H, s) 1.85-2.05(2H, m) 1.15-1.70(15H, m)0.77(6H, t, J=6.9Hz) 64

61.0-65.0 8.40(1H, dd, J=1.5, 8.4Hz) 7.92(1H, brs) 7.49(1H, ddd, J=1.5,7.8, 8.4Hz) 7.39(1H, dd, J=1.5, 7.8Hz) 7.33(2H, m) 7.15(1H, dt, J=1.5,7.8Hz) 6.96(2H, m) 4.80(2H, s) 1.85-2.00(2H, m) 1.20-1.80(11H, m)0.86(6H, d, J=6.6Hz) 65

61.0-64.0 8.38(1H, dd, J=1.5, 8.4Hz) 8.02(1H, brs) 7.47(1H, ddd, J=1.5,7.8, 8.4Hz) 7.37(1H, dd, J=1.5, 7.8Hz) 7.12(1H, dt, J=1.5, 7.8Hz)4.59(1H, m) 3.88(1H, m) 3.17(1H, m) 2.92(1H, m) 2.78(1H, m)1.90-2.20(4H, m) 2.11(3H, s) 1.20-1.85(13H, m) 0.87(6H, d, J=6.6Hz)

[0530] The compounds 25-1 through 25-109 shown in Tables 18 through wereobtained in the same manner as in Examples 25 through 28. TABLE 18 No.Compound 25-1

25-2

25-3

25-4

25-5

25-6

25-7

25-8

25-9

25-10

25-11

25-12

[0531] TABLE 19 No. Compound 25-13

25-14

25-15

25-16

25-17

25-18

25-19

25-20

25-21

25-22

25-23

25-24

[0532] TABLE 20 No. Compound 25-25

25-26

25-27

25-28

25-29

25-30

25-31

25-32

25-33

25-34

25-35

25-36

[0533] TABLE 21 No. Compound 25-37

25-38

25-39

25-40

25-41

25-42

25-43

25-44

25-45

25-46

25-47

25-48

[0534] TABLE 22 No. Compound 25-49

25-50

25-51

25-52

25-53

25-54

25-55

25-56

25-57

25-58

25-59

25-60

[0535] TABLE 23 No. Compound 25-61

25-62

25-63

25-64

25-65

25-66

25-67

25-68

25-69

25-70

25-71

25-72

[0536] TABLE 24 No. Compound 25-73

25-74

25-75

25-76

25-77

25-78

25-79

25-80

25-81

25-82

25-83

25-84

[0537] TABLE 25 No. Compound 25-85

25-86

25-87

25-88

25-89

25-90

25-91

25-92

25-93

25-94

25-95

25-96

[0538] TABLE 26 No. Compound 25-97 

25-98 

25-99 

25-100

25-101

25-102

25-103

25-104

25-105

25-106

25-107

25-108

[0539] TABLE 27 No. Compound 25-109

Example 66

[0540] Synthesis ofS-(4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate (formula (I); R=1-isopropylcyclohexyl, X₁,X₄=a hydrogen atom, X₂, X₃=a chlorine atom, Y=carbonyl, Z=pivaloyl).

[0541] Step 4) A tetrahydrofuran (0.5 ml)-methanol (1 ml) solutioncontainingS-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)phenyl]N,N-dimethylthiocarbamate (86 mg) obtained in the same manner as in thestep 9) of Example 19 and potassium hydroxide (50 mg) was refluxed for30 minutes under heating. After the solution was allowed to cool, waterwas added and the aqueous layer was washed with hexane. Then, theaqueous layer was acidified with potassium hydrogensulfate, and wasextracted with chloroform (10 ml). Pyridine (90 μl) was added to theresulting extract, and pivaloyl chloride (41 μl) was further added tothe extract at room temperature under stirring. The solution was stirredfor 1 hour. After concentration, the residue was purified by silica gelcolumn chromatography (a developing solvent; hexane:ethyl acetate=20:1)toobtainthedesired compound (24 mg, yield: 27%).

EXAMPLES 67-81

[0542] The compounds shown in Tables 28-30 were obtained in the samemanner as in Example 66. TABLE 28 Example Compound m.p. (° C.) ¹H NMR(CDCl₃ 300MHz) 66

92-92 8.75(1H, s) 8.01(1H, brs) 7.44(1H, s) 1.95-2.10(2H, m)1.10-1.75(9H, m) 1.34(9H, s) 0.91(6H, d, J=6.6Hz) 67

95-96 8.73(1H, s) 8.10(1H, brs) 7.44(1H, s) 1.85-2.00(2H, m)1.10-1.70(8H, m) 1.34(9H, s) 0.89(6H, m) 0.35-0.47(4H, m) 68

109-110 8.67(1H, s) 7.61(1H, brs) 7.44(1H, s) 2.06(1H, quint, J=7.2Hz)0.85-1.85(11H, m) 1.36(9H, s) 1.18(3H, d, J=6.6Hz) 69

109-110 8.71(1H, s) 8.01(1H, brs) 7.44(1H, s) 1.95-2.05(2H, m)1.05-1.70(18H, m) 1.35(9H, s) 0.84(3H, t, J=6.7Hz) 0.84(6H, d, J=6.6Hz)70

116-117 8.76(1H, s) 8.11(1H, brs) 7.44(1H, s) 2.02-2.15(2H, m)1.20-1.65(8H, m) 1.34(9H, s) 0.55-0.65(1H, m) 0.35-0.45(2H, m)0.01-0.02(4H, m) 71

111-112 8.70(1H, s) 8.03(1H, brs) 7.44(1H, s) 1.90-2.10(2H, m)0.75-1.75(21H, m) 1.36(9H, s)

[0543] TABLE 29 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300MHz) 72

101-102 8.70(1H, s) 7.92(1H, brs) 7.43(1H, s) 2.00-2.15(2H, m)1.30-1.65(13H, m) 1.35(9H, s) 1.05-1.15(2H, m) 0.85(6H, d, J=6.6Hz) 73

53-54 8.70(1H, s) 7.68(1H, brs) 7.44(1H, s) 2.35-2.50(2H, m)1.25-2.05(7H, m) 1.34(9H, s) 1.05-1.15(2H, m) 0.88(6H, d, J=6.6Hz) 74

93.0-93.5 9.39(1H, d, J=2.4Hz) 8.20(1H, brs) 7.93(1H, dd, J=2.4, 8.4Hz)7.53(1H, d, J=8.4Hz) 1.95-2.15(2H, m) 1.00-1.75(13H, m) 1.37(9H, s)0.85(6H, d, J=6.6Hz) 75

103-104 8.85(1H, d, J=1.5Hz) 8.14(1H, brs) 7.46(1H, d, J=7.8Hz) 7.35(1H,dd, J=1.5, 7.8Hz) 1.95-2.15(2H, m) 1.00-1.75(13H, m) 1.36(9H, s)0.85(6H, d, J=6.6Hz) 76

77-78 8.57(1H, d, J=2.7Hz) 8.06(1H, brs) 7.27(1H, d, J=7.8Hz) 7.08(1H,dd, J=2.7, 7.8Hz) 1.95-2.10(2H, m) 1.05-1.65(13H, m) 1.34(9H, s)0.84(6H, d, J=6.6Hz) 77

80-82 8.38(1H, d, J=8.7Hz) 7.99(1H, brs) 7.40(1H, dd, J=2.7, 8.7Hz)7.35(1H, d, J=2.7Hz) 1.90-2.05(2H, m) 1.05-1.65(13H, m) 1.35(9H, s)0.84(6H, d, J=6.6Hz)

[0544] TABLE 30 Example Compound m.p. (° C.) ¹H NMR (CDCl₃ 300MHz) 78

76-77 8.20(1H, d, J=2.7Hz) 8.09(1H, brs) 7.22(1H, d, J=8.4Hz) 6.66(1H,dd, J=2.7, 8.4Hz) 3.85(3H, s) 1.95-2.05(2H, m) 1.05-1.65(13H, m)1.34(9H, s) 0.84(6H, d, J=6.6Hz) 79

55-56 8.34(1H, dd, J=3.0, 11.4Hz) 8.11(1H, brs) 7.31(1H, dd, J=6.3,8.4Hz) 6.81(1H, ddd, J=3.0, 8.4, 11.4Hz) 1.95-2.15(2H, m) 1.05-1.65(13H,m) 1.34(9H, s) 0.84(6H, d, J=6.6Hz) 80

97-98 8.44(1H, dd, J=8.1, 12.9Hz) 7.98(1H, brs) 7.19(1H, dd, J=8.4,9.6Hz) 1.95-2.05(2H, m) 1.05-1.65(13H, m) 11.34(9H, s) 0.84(6H, d,J=6.6Hz) 81

94-95 8.29-8.35(1H, m) 7.90(1H, brs) 7.09-7.19(2H, m) 1.92-2.06(2H, m)1.09-1.55(13H, m) 1.35(9H, s) 0.85(6H, d, J=6.6Hz)

[0545] The compounds 66-1 through 66-53 shown in Tables 31 through 35were also obtained in the same manner as in Example 66. TABLE 31 No.Compound 66-1

66-2

66-3

66-4

66-5

66-6

66-7

66-8

66-9

 66-10

 66-11

 66-12

[0546] TABLE 32 No. Compound 66-13

66-14

66-15

66-16

66-17

66-18

66-19

66-20

66-21

66-22

66-23

66-24

[0547] TABLE 33 No. Compound 66-25

66-26

66-27

66-28

66-29

66-30

66-31

66-32

66-33

66-34

66-35

66-36

[0548] TABLE 34 No. Compound 66-37

66-38

66-39

66-40

66-41

66-42

66-43

66-44

66-45

66-46

66-47

66-48

[0549] TABLE 35 No. Compound 66-49

66-50

66-51

66-52

66-53

82-1 

EXAMPLE 82

[0550] Synthesis ofbis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]disulfide (formula (I); R=1-isopentylcyclohexyl, X₁, X₄=a hydrogen atom,X₂, X₃=a chlorine atom, Y=carbonyl,Z=4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)phenylthio)

[0551] Step 10)N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide(formula (III-2); R=1-isopentylcyclohexyl, X₁, X₄=a hydrogen atom, X₂,X₃=a chlorine atom, Y=carbonyl)

[0552] A tetrahydrofuran (2 ml)-methanol (1 ml) solution containingS-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]N,N-dimethylthiocarbamate (400 mg) obtained in the same manner as instep 9 of Example 19 and. potassium hydroxide (180 mg) was refluxed for2 hours under heating and the resulting mixture was allowed to cool.After adding water thereto, the aqueous layer was washed with hexane,was acidified with a saturated aqueous potassium hydrogensulfate, andwas extracted with chloroform. The organic layer was washed with waterand a saturated brine, and dried over anhydrous sodium sulfate. Afterremoving anhydrous sodium sulf ate by filtration, the organic solventwas distilled off under reduced pressure to obtain the crude compound.

[0553] Step 3) A dimethyl sulf oxide solution (5 ml) of the crudeproduct obtained in the above step 10) was stirred for 2 hours at 130°C. and the mixture was allowed to cool. Water was added to the solution,which was extracted with chloroform. The organic layer was washed withwater and saturated brine, and dried over anhydrous sodium sulfate. Theresidue obtained after concentration was purified by silica gel columnchromatography (a developing solvent; hexane:ethyl acetate=30:1) toobtain the compound (200 mg, yield: 60%). TABLE 36 Example Compound m.p.(° C.) ¹H NMR (CDCl₃ 300 MHz) 82

Amorphous 8.78(2H, s) 8.38(2H, brs) 7.24(2H, s) 1.80-2.00(4H, m)1.00-1.75(26, m) 0.86(12H, d, J=6.6Hz)

[0554] The compound 82-1 shown in Table 35 was obtained in the samemanner as in Example 82.

EXAMPLE 83

[0555] Synthesis of 2-tetrahydrofurylmethyl2-(1-isopentylcyclohexanecarbonylamino)phenyl disulfide (formula (I);R=1-isopentylcyclohexyl, X₁, X₂, X₃, X₄=a hydrogen atom, Y=carbonyl,Z=2-tetrahydrofurfurylmethylthio)

[0556] Step 5) An ethanol (6 ml)-water (6 ml) solution containingtetrahydrofurfuryl chloride (3.0 g) and sodium thiosulfate (4.13 g) wasrefluxed for 17 hours under heating and the mixture was allowed to cool.Ethanol was removed under reduced pressure and an aqueous solution ofBunte salt was obtained. An aqueous solution (1 ml) ofN-(2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide (380 mg) obtainedas in Example 11 and sodium hydroxide (50 mg) was added dropwise to thesolution at 0° C. and the solution was stirred for 1.5 hour. Afteraddition of ether, the organic layer was successively washed with anaqueous sodium hydroxide, water, and a saturated brine, and dried overanhydrous sodium sulfate. The residue obtained by concentration underreduced pressure was purified by silica gel column chromatography (adeveloping solvent: hexane:ethyl acetate=8:1) to obtain the desiredcompound (128 mg, yield: 24%).

EXAMPLE 84

[0557] Synthesis of phenyl 2-pivaloylaminophenyl disulfide (formula (I);R=t-butyl, X₁, X₂, X₃, X₄=a hydrogen atom, Y=carbonyl, Z=phenylthio)

[0558] Step 5′) Trimethylsilane-imidazole (202 mg) was added to a carbontetrachloride solution (5 ml) containing thiophenol (159 mg). Thesolution was stirred for 2 hours at room temperature. The depositedimidazole was filtered off to obtain a solution.

[0559] Then, sulfuryl chloride (97 mg) and triethylamine (1 drop) weresuccessively added to a carbon tetrachloride solution (5 ml) containingbis-[2-(pivaloylamino)phenyl] disulfide (300 mg) obtained as in the step1 of Example 1 at 0° C. The solution was stirred for 1.5 hour at thesame temperature and was added dropwise to the above solution cooled inan ice-salt bath and the mixture was continuously stirred for 2.5 hour.After completion of the reaction, water was added and the solution wasextracted with chloroform. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure and the resulting residue was purified by silicagel column chromatography (a developing solvent; hexane:ethylacetate=12:1) to obtain the desired compound (337 mg, yield: 74%). TABLE37 Example Compound m.p. (° C.) ¹H NMR(CDCl₃ 300MHz) 83

Oil 8.53(1H, brs) 8.44(1H, dd, J=1.5, 8.4Hz) 7.58(1H, dd, J=1.5, 7.8Hz)7.40(1H, ddd, J=1.5, 7.8, 8.4Hz) 7.04(1H, dt, J=1.5, 7.8Hz) 4.14(2H,quint, J=6.6Hz) 3.86(1H, dt, J=8.4, 6.6Hz) 3.77(1H, dt, J=8.4, 6.6Hz)2.96(1H, dd, J=6.6, 13.2Hz) 2.84(1H, dd, J=6.6, 13.2Hz) 1.80-2.20(5H, m)1.10-1.75(14H, m) 0.86(6H, d, J=6.6Hz) 84

Oil 8.51(1H, brs) 8.40(1H, dd, J=1.5, 8.4Hz) 7.20-7.50(7H, m) 6.97(1H,dt, J=1.5, 7.8Hz) 1.30(9H, s)

[0560] In the following, the results of the test for the CETP activityinhibitory effect of the compounds of the present invention are shown.

TEST EXAMPLES

[0561] (1) Preparation of Donor Lipoprotein

[0562] Potassium bromide (KBr) was added to the plasma of healthysubjects (40 ml) to adjust specific gravity to d=1.125 g/ml. Densitygradient centrifugation (227,000× g, 4° C., 17 hours) was conducted toobtain a fraction with specific gravity d>1.125 g/ml (HDL₃fraction). Thefraction thus obtained was dialyzed against a PBS solution [10 mMNa₂HPO₄/10 mM NaH₂PO₄/0.15 M NaCl/1 mM EDTA (pH 7.4)]. Then,tritium-labeled cholesterol (10 nM) (50.3 Ci/mM) was dissolved in 95%ethanol and added gradually to the above HDL₃ fraction under stirring.The solution was incubated for 18 hours at 37° C. [Tritium-labeledcholesterol was esterified by this procedure by the action oflecithin:cholesterol acyltransferase (LCAT) present on the surface ofHDL₃ and taken up into the interior of HDL₃ as tritium-labeledcholesterylester ([³H]CE)]. After incubation, KBr was added and specificgravity was adjusted to d=1.21 g/ml. Density gradient centrifugation(227,000× g, 4° C., 17 hours) was conducted and the fraction with d<1.21g/ml was harvested. The fraction thus obtained was dialyzed against theabove PBS solution to obtain HDL₃ that took up [³H] CE ([³H]CE-HDL₃Ispecific gravity: 1.125<d <1.21, specific activity: 101,000 dpm/nM),which served as donor lipoprotein.

[0563] (2) Preparation of Acceptor Lipoprotein

[0564] Physiological saline (specific gravity d=1.006 g/ml) was layeredupon the plasma of healthy subjects (100 ml). Density gradientcentrifugation (227,000× g, 4° C., 4 hours) was conducted and thefraction with specific gravity d>1.006 g/ml was harvested. KBr was addedto the fraction thus obtained to adjust specific gravity to d=1.063 g/mland density gradient centrifugation (227,000× g, 4° C., 20 hours) wasconducted to harvest the fraction with specific gravity d>1.063 g/ml.The thus-obtained fraction was dialyzed against the above PBS solutionto obtain fractions containing IDL and LDL (specific gravity: 1.006<d<1.063), which served as acceptor lipoprotein.

TEST EXAMPLE 1 In Vitro CETP Activity Inhibitory Effect in Whole Plasma

[0565] Plasma containing [³H] CE-HDL₃ (600,000 dpm/ml) was prepared byadding donor lipoprotein obtained in the above (1) to plasma fromhealthy subjects. A sample solution was prepared using a 1:1 solution ofN-methylpyrrolidone and polyethyleneglycol 400 as a solvent. The samplesolution or the solvent alone (2 μl) and the plasma containing[³H]CE-HDL₃ (100 μl) were added to microtubes and incubated for 4 hoursat 37° C. or 4° C. After ice cooling, a TBS solution [20 mM Tris/0.15 MNaCl (pH 7.4)] containing 0.15 Mmagnesium chloride and 0.3% dextransulfate (100 μl) were added to each microtube and mixed well. Afterallowing the microtubes to stand at 4° C. for 30 minutes, centrifugation(8,000 rpm, 4° C., 10 minutes) was conducted and the radioactivity ofthe resulting supernatant (HDL fraction) was determined with ascintillation counter. The difference between the values obtained afterincubation at 4° C. and 37° C. with the solvent alone was regarded asCETP activity and a decrease (%) of the measured values produced by thesamples was regarded as inhibition rate (%) of CETP activity. Based onthe inhibition rate (%) of CETP activity, IC₅₀ value of each sample wascalculated.

[0566] The results are shown in Tables 38-48.

TEST EXAMPLE 2 Ex Vivo CETP Activity Inhibitory Effect of Plasma fromTransgenic Mice

[0567] Samples were suspended in a 0.5% methylcellulose solution andadministered orally using a plastic probe to transgenic mice havingintroduced human CETP gene (hereafter referred to as mice; preparedusing the method described in Japanese Patent Application No. Hei8-130660), which had been fasted overnight. Blood was collected beforeadministration, and 6 hours after administration CETP activity in theplasma was determined using the following method.

[0568] Donor lipoprotein ([³H]CE-HDL₃, containing 0.21 μg cholesterol)obtained in the above (1), acceptor lipoprotein obtained in the above(2) (containing 21 μg of cholesterol), and 0.9 μl of mice plasma wereadded to microtubes. A total volume was adjusted to 600 μl/tube with aTBS solution [10 mM Tris/0.15 M NaCl (pH 7.4)]. The microtubes wereincubated for 15 hours at 37° C. or 4° C. Then, an ice-cooled TBSsolution (400 μl/tube) and a 0.3% dextran sulfate solution (100 μl/tube)containing 0.15 M magnesium chloride were added to the microtubes andmixed well. After allowing the microtubes to stand for 30 minutes at 4°C., centrifugation (8,000 rpm, 4° C., 10 minutes) was carried out andradioactivity of the resulting supernatant (HDL fraction) was determinedwith a scintillation counter. The difference between measured valuesobtained by incubating plasma of individual mice at 4° C. and 37° C.before administration of the samples were regarded as CETP activity anda decrease (%) of measured values after administration of samples wasregarded as inhibition rate (%) of CETP activity.

[0569] The results are shown in Tables 38-48. TABLE 38 CETP activityinhibitory rate in plasma CETP activity from transgenic mouse (%)inhibition in 100 300 whole plasma 10 mg/kg, 30 mg/kg, mg/kg, mg/kg,Example IC₅₀ (μM) p.o. p.o. p.o. p.o. 1 20 3 101 4 175 5 3 6 5 7 2 8 325 9 99 11 5 27 45 57 12 17 13 5 14 8 9 15 12 16 8 17 8 18 6 19 179 2016 21 9 22 56 22 44

[0570] TABLE 39 CETP activity inhibitory rate in plasma CETP activityfrom transgenic mouse (%) inhibition in 100 300 whole plasma 10 mg/kg,30 mg/kg, mg/kg, mg/kg, Example IC₅₀ (μM) p.o. p.o. p.o. p.o. 23 18 2429 29 25 11 19 45 52 26 7 44 27 7 31 28 6 36 30 72 31 32 32 32 33 61 2339 52 55 34 9 4 35 4 36 16 19 37 7 18 42 47 38 6 15 40 39 11 17 41 40 2320 48 64 41 7 27 42 42 9 31 38 43 49

[0571] TABLE 40 CETP activity inhibitory rate in plasma CETP activityfrom transgenic mouse (%) inhibition in 100 300 whole plasma 10 mg/kg,30 mg/kg, mg/kg, mg/kg, Example IC₅₀ (μM) p.o. p.o. p.o. p.o. 44 23 45 718 36 46 5 22 48 47 6 31 48 49 31 50 49 6 29 50 2 51 16 52 8 8 53 8 5412 55 65 56 13 34 57 41 59 4 44 60 41 44 61 4 38 62 4 38 63 4 43 64 4 34

[0572] TABLE 41 CETP activity inhibitory rate in plasma CETP activityfrom transgenic mouse (%) inhibition in 100 300 whole plasma 10 mg/kg,30 mg/kg, mg/kg, mg/kg, Example IC₅₀ (μM) p.o. p.o. p.o. p.o. 66 7 67 968 10 69 6 70 4 71 4 72 74 73 37 74 14 5 75 25 1 76 18 4 77 17 1 78 1179 60 14 26 80 6 12 81 21 10 82 7 83 5 84 158

[0573] TABLE 42 CETP activity inhibitory rate in plasma CETP activityfrom transgenic mouse (%) inhibition in 100 300 whole plasma 10 mg/kg,30 mg/kg, mg/kg, mg/kg, No. IC₅₀ (μM) p.o. p.o. p.o. p.o. 1-1 41 1-2 251-6 22 1-7 24 1-8 21  1-12 12  1-13 18 19-1  19 19-2  33 19-5  17 19-6 18 25-4  32 25-7  46 25-8  25 25-12 33 25-13 28 25-14 30 25-16 41 25-1723 25-18 19

[0574] TABLE 43 CETP activity inhibitory rate in plasma CETP activityfrom transgenic mouse (%) inhibition in 100 300 whole plasma 10 mg/kg,30 mg/kg, mg/kg, mg/kg, No. IC₅₀ (μM) p.o. p.o. p.o. p.o. 25-19 22 25-2048 25-21 28 25-22 27 25-23 25 25-25 24 25-26 22 25-27 21 25-28 21 25-3021 25-31 21 25-32 20 25-33 18 25-34 21 25-35 27 25-36 30 25-37 24 25-3820 25-39 22 25-40 23

[0575] TABLE 44 CETP activity inhibitory rate in plasma CETP activityfrom transgenic mouse (%) inhibition in 100 300 whole plasma 10 mg/kg,30 mg/kg, mg/kg, mg/kg, No. IC₅₀ (μM) p.o. p.o. p.o. p.o. 25-41 26 25-4222 25-44 9 25-45 13 21 25-46 9 35 25-47 29 25-48 23 25-49 21 16 25-52 6819 40 25-53 7 26 25-54 6 25-55 10 25-56 7 24 25-57 7 18 46 25-59 8 20 3725-60 5 25-61 5 28 25-63 21 25 25-64 20 25-65 9

[0576] TABLE 45 CETP activity inhibitory rate in plasma CETP activityfrom transgenic mouse (%) inhibition in 100 300 whole plasma 10 mg/kg,30 mg/kg, mg/kg, mg/kg, No. IC₅₀ (μM) p.o. p.o. p.o. p.o. 25-66 35 25-6740 25-72 27 25-76 36 25-77 7 25-78 11 25-79 6 25-80 5 25-81 14 25-82 1725-83 18 25-84 10 17 25-85 7 25-86 10 25-87 6 25-91 22 25-92 19 25-93 2225-94 18 25-95 18

[0577] TABLE 46 CETP activity inhibitory rate in plasma CETP activityfrom transgenic mouse (%) inhibition in 100 300 whole plasma 10 mg/kg,30 mg/kg, mg/kg, mg/kg, No. IC₅₀ (μM) p.o. p.o. p.o. p.o. 25-96 8 25-979 19 25-98 8 25-99 6 25-100 16 25 25-101 7 8 25-102 8 9 25-103 12 25-1049 25-105 6 14 25-106 10 29 25-107 11 22 25-108 7 8 66-3 24 66-4 28 66-99 66-10 23 66-11 22 66-12 17 66-14 11

[0578] TABLE 47 CETP activity inhibitory rate in plasma CETP activityfrom transgenic mouse (%) inhibition in 100 300 whole plasma 10 mg/kg,30 mg/kg, mg/kg, mg/kg, No. IC₅₀ (μM) p.o. p.o. p.o. p.o. 66-16 8 66-1718 66-18 11 66-21 41 66-22 19 66-23 13 66-24 12 66-25 19 66-26 8 66-27 966-28 18 66-29 7 66-30 19 66-31 27 66-32 22 66-33 19 66-34 22 66-38 2666-40 42 66-41 25

[0579] TABLE 48 CETP activity CETP activity inhibitory rate ininhibition in plasma from transgenic mouse (%) whole plasma 10 mg/kg, 30mg/kg, 100 mg/ 300 mg/kg, No. IC₅₀ (μM) p.o. p.o. kg, p.o. p.o. 66-42 1066-43 23 66-46 35 66-48 11 66-49 40 66-51 45 66-52 46 66-53 15 82-1  5

INDUSTRIAL APPLICABILITY

[0580] The above test results reveal that the compounds (I) of thepresent invention have an excellent CETP activity inhibitory effect.Thus, the compounds can reduce IDL, VLDL, and LDL, which aggravateatherosclerosis, and increase HDL that acts inhibitory thereto, and,therefore, are useful as a conventionally unknown, new type of apreventive or therapeutic agent for hyperlipidemia. The compound is alsouseful as a preventive or therapeutic agent for atheroscleroticdiseases.

1. A CETP activity inhibitor comprising as an active ingredient acompound represented by formula (I):

wherein R represents a straight chain or branched C₁₋₁₀ alkyl group; astraight chain or branched C₂₋₁₀ alkenyl group; a halo-C₁₋₄ lower alkylgroup; a substituted or unsubstituted C₃₋₁₀ cycloalkyl group; asubstituted or unsubstituted C₅₋₈ cycloalkenyl group; a substituted orunsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group; a substituted orunsubstituted aryl group; a substituted or unsubstituted aralkyl group;or a substituted or unsubstituted 5- or 6-membered heterocyclic grouphaving 1-3 nitrogen, oxygen, or sulfur atoms, X₁, X₂/X₃/and X₄ may bethe same or different and represents a hydrogen atom; a halogen atom; aC₁₋₄ lower alkyl group; a halo-C₁₋₄ lower alkyl group; a C₁₋₄ loweralkoxy group; a cyano group; a nitro group; an acyl group; or an arylgroup, Y represents —CO—; or —SO₂, and Z represents a hydrogen atom; ora mercapto-protecting group selected from the group consisting of a C₁₋₄lower alkoxymethyl group, a C₁₋₄ lower alkylthiomethyl group, anaralkyloxymethyl group having an aryl group selected from phenyl,biphenyl, and naphthyl, an aralkylthiomethyl group having an aryl groupselected from phenyl, biphenyl, and naphthyl, a C₃₋₁₀cycloalkyloxymethyl group, a C₅₋₈ cycloalkenyloxymethyl group, a C₃₋₁₀cycloalkyl C₁₋₁₀ alkoxymethyl group, an aryloxymethyl group having anaryl group selected from phenyl, biphenyl, and naphthyl, anarylthiomethyl group having an aryl group selected from phenyl,biphenyl, and naphthyl, an acyl group, an acyloxy group, anaminocarbonyloxymethyl group, a thiocarbonyl group, and a thio group,provided that R is not a methyl group when Y is —CO—, or a prodrugcompound, a pharmaceutically acceptable salt, a hydrate, or a solvatethereof.
 2. The CETP activity inhibitor comprising as an activeingredient the compound as claimed in claim 1, wherein R represents astraight chain or branched C₁₋₁₀ alkyl group; a straight chain orbranched C₂₋₁₀ alkenyl group; a halo-C₁₋₄ lower alkyl group substitutedwith 1-3 halogen atoms selected from fluorine, chlorine, and bromine; aC₃₋₁₀cycloalkyl group, a C₅₋₈ cycloalkenyl group, or a C₃₋₁₀ cycloalkylC₁₋₁₀ alkyl group, each of which may have 1-4 substituents selected fromthe group consisting of a straight chain or branched C₁₋₁₀ alkyl group,a straight chain or branched C₂₋₁₀ alkenyl group, a C₃₋₁₀ cycloalkylgroup, a C₅₋₈ cycloalkenyl group, a C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group,an aryl group selected from phenyl, biphenyl, and naphthyl, an oxogroup, and an aralkyl group having an aryl group selected from phenyl,biphenyl, and naphthyl; or an aryl, aralkyl, or 5- or 6-memberedheterocyclic group with 1-3 nitrogen, oxygen or sulfur atoms, each ofwhich may have 1-4 substituents selected from the group consisting of astraight chain or branched C₁₋₁₀ alkyl group, a straight chain orbranched C₂₋₁₀ alkenyl group, a halogen atom selected from fluorine,chlorine, and bromine, a nitro group, and a halo-C₁₋₄ lower alkyl grouphaving a halogen atom selected from fluorine, chlorine, and bromine; ora prodrug compound thereof, a pharmaceutically acceptable salt, ahydrate, or a solvate thereof.
 3. The CETP activity inhibitor comprisingas an active ingredient the compound as claimed in claim 2, which isrepresented by the formula (I-1):

wherein R represents a straight chain or branched C₁₋₁₀ alkyl group; astraight chain or branched C₂₋₁₀ alkenyl group; a halo-C₁₋₄ lower alkylgroup substituted with 1-3 halogen atoms selected from fluorine,chlorine, and bromine; a C₃₋₁₀cycloalkylgroup, a C₅₋₈cycloalkenylgroup,or a C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group, each of which may have 1-4substituents selected from the group consisting of a straight chain orbranched C₁₋₁₀ alkyl group, a straight chain or branched C₂₋₁₀ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₅₋₈ cycloalkenyl group, a C₃₋₁₀cycloalkyl C₁₋₁₀ alkyl group, an aryl group selected from phenyl,biphenyl, and naphthyl, an oxo group, and an aralkyl group having anaryl group selected from phenyl, biphenyl, and naphthyl; or an aryl,aralkyl, or 5- or 6-membered heterocyclic group with 1-3 nitrogen,oxygen or sulfur atoms, each of which may have 1-4 substituents selectedfrom the group consisting of a straight chain or branched C₁₋₁₀ alkylgroup, a straight chain or branched C₂₋₁₀ alkenyl group, a halogen atomselected from fluorine, chlorine, and bromine, a nitro group, and ahalo-C₁₋₄ lower alkyl group having a halogen atom selected fromfluorine, chlorine, and bromine; X₁, X₂, X₃, and X₄ may be the same ordifferent and represents a hydrogen atom; a halogen atom; a C₁₋₄ loweralkyl group; a halo-C₁₋₄ lower alkyl group; a C₁₋₄ lower alkoxy group; acyano group; a nitro group; an acyl group; or an aryl group, Yrepresents —CO—; or —SO₂, and Z, represents a hydrogen atom; a grouprepresented by the formula

wherein R, X₁, X₂, X₃, X₄, and Y are the same as described above; —Y,R₁,wherein Y₁ represents —CO—; or —CS—, and R₁ represents a substituted orunsubstituted straight chain or branched C₁₋₁₀ alkyl group; a C₁₋₄ loweralkoxy group; a C₁₋₄ lower alkylthio group; a substituted orunsubstituted amino group; a substituted or unsubstituted ureido group;a substituted or unsubstituted C₃₋₁₀ cycloalkyl group; a substituted orunsubstituted C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group; a substituted orunsubstituted aryl group; a substituted or unsubstituted aralkyl group;a substituted or unsubstituted arylalkenyl group; a substituted orunsubstituted arylthio group; a substituted or unsubstituted 5- or6-membered heterocyclic group having 1-3 nitrogen, oxygen, or sulfuratoms; or a substituted or unsubstituted 5- or 6-memberedheteroarylalkyl group; or —S—R₂, wherein R₂ represents a substituted orunsubstituted C₁₋₄ lower alkyl group; or a substituted or unsubstitutedaryl group, or a prodrug compound, a pharmaceutically acceptable salt, ahydrate, or a solvate thereof.
 4. The CETP activity inhibitor comprisingas an active ingredient the compound as claimed in claim 3, wherein R₁represents a straight chain or branched C₁lo alkyl group which may have1-3 substituents selected from the group consisting of a halogen atomselected from fluorine, chlorine, and bromine, a C₁₋₄ lower alkoxygroup, an amino group that may be substituted with a C₁₋₄ lower alkyl,acyl, or hydroxyl group, a C₁₋₄ lower alkylthio group, a carbamoylgroup, a hydroxyl group, an acyl group, an acyloxy group having an acylgroup, a carboxyl group, and an aryloxy group that may be substitutedwith a halogen atom selected from fluorine, chlorine, and bromine; a C₁₄lower alkoxy group; a C₁₋₄ lower alkylthio group; an amino or ureidogroup that may have 1-2 substituents selected from the group consistingof a C₁₋₄ lower alkyl group, a hydroxyl group, an acyl group, and anaryl group that may be substituted with a lower C₁₋₄ alkoxy group; aC₃₋₁₀ cycloalkyl or C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl group that may havesubstituents selected from the group consisting of a straight orbranched C₁lo alkyl group, a C₃₋₁₀ cycloalkyl group, a C₅₋₈ cycloalkenylgroup, an aryl group, an amino group, a C₁₋₄ lower alkylamino grouphaving a C₁₋₄ lower alkyl group, and an acylamino group having an acylgroup; an aryl group, an aralkyl group, an arylalkenyl group, or anarylthio group, each of which may have 1-4 substituents selected fromthe group consisting of a C₁₋₁₀ alkyl group, a halogen atom selectedfrom fluorine, chlorine, and bromine, a nitro group, a hydroxyl group, aC₁₋₄ lower alkoxy group, a C₁₋₄ lower alkylthio group, an acyl group, ahalo-C₁₋₄ lower alkyl group having a halogen atom selected fromfluorine, chlorine, and bromine, and an amino group that may besubstituted with a C₁₋₄ lower alkyl or acyl group; a 5- or 6-memberedheterocyclic group having 1-3 nitrogen, oxygen or sulfur atoms or a 5-or 6-membered heteroarylalkyl group that may have 1-4 substituentsselected from the group consisting of a straight chain or branched C₁₋₁₀alkyl group, a halogen atom selected from fluorine, chlorine, andbromine, an acyl group, an oxo group, and an halo-C₁₋₄ lower alkyl grouphaving a halogen atom selected from fluorine, chlorine, and bromine; andR₂ represents a C₁₋₄ lower alkyl groups that may have 1-3 substituentsselected from the group consisting of a C₁₋₄ lower alkoxy group, anamino group that may be substituted with a C₁₋₄ lower alkyl or acylgroup, a C₁₋₄ lower alkylthio group, a carbamoyl group, a hydroxylgroup, a carboxyl group, an acyl group, and a 5- or 6-memberedheterocyclic group having 1-3 nitrogen, oxygen, or sulfur atoms; or anaryl group that may have 1-4 substituents selected from the groupconsisting of a C₁₋₄ lower alkyl group, a halogen atom selected fromfluorine, chlorine, and bromine, a nitro group, a hydroxyl group, a C₁₋₄lower alkoxy group, a C₁₋₄ lower alkylthio group, an acyl group, anamino group that may be substituted with a Cl-4 lower alkyl or acylgroup, and a halo-C₁l₄ lower alkyl group having a halogen atom selectedfrom fluorine, chlorine, and bromine, or a prodrug compound, apharmaceutically acceptable salt, a hydrate, or a solvate thereof. 5.The CETP activity inhibitor comprising as an active ingredient thecompound as claimed in claim 1, which is selected from the groupconsisting of bis-[2-(pivaloylamino)phenyl] disulfide;bis-[2-(2-propylpentanoylamino)phenyl] disulfide;bis-[2-(1-methylcyclohexanecarbonylamino)phenyl] disulfide;bis-[2-(1-isopentylcyclopentanecarbonylamino)phenyl] disulfide;bis-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] disulfide;N-(2-mercaptophenyl)-2,2-dimethylpropioneamide;N-(2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide;N-(2-mercaptophenyl)-1-methylcyclohexanecarboxamide;N-(2-mercaptophenyl)-1-isopentylcyclopentanecarboxamide;N-(2-mercaptophenyl)-1-isopropylcyclohexanecarboxamide;N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide;N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclopentanecarboxamide;N-(2-mercapto-5-methylphenyl)-1-isopentylcyclohexanecarboxamide;N-(2-mercapto-4-methylphenyl)-1-isopentylcyclohexanecarboxamide;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thioacetate;S-[2-(1-methylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;S-[2-(pivaloylamino)phenyl]phenylthioacetate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-3-phenylthiopropionate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]3-pyridinethiocarboxylate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] chloro-thioacetate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] methoxy-thioacetate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] thio-propionate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] phenoxy-thioacetate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-methylthiopropionate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]4-chlorophenoxythioacetate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclo-propanethiocarboxylate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-acetylamino-4-carbamoylthiobutyrate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]2-hydroxy-2-methylthiopropionate;S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]2,2-dimethylthiopropionate;S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl] thio-acetate;S-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;S-[4,5-dichloro-2-(1-isopentylcyclopentanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;S-[2-(1-isopentylcyclohexanecarbonylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate; O-methylS-[2-(1-isopentylcyclohexanecarbonylamino)phenyl monothiocarbonate;S-[2-(1-methylcyclohexanecarbonylamino)phenyl]S-phenyl dithiocarbonate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] N-phenylthiocarbamate;S-[2-(pivaloylamino)-4-trifluoromethylphenyl]2,2-dimethylthiopropionate;S-[4,5-dichloro-2-(1-cyclopropylcyclohexanecarbonylamino) phenyl]2,2-dimethylthiopropionate;S-[4,5-dichloro-2-(2-cyclohexylpropionylamino)phenyl]2,2-dimethylthiopropionate;S-[4,5-dichloro-2-(1-pentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;S-[4,5-dichloro-2-(1-cyclopropylmethylcyclohexane carbonylamino)phenyl]2,2-dimethylthiopropionate;S-[4,5-dichloro-2-(1-cyclohexylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;S-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;S-[4,5-dichloro-2-(1-isopentylcycloheptanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;S-[4,5-dichloro-2-(1-isopentylcyclobutanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;S-[2-(1-isopentylcyclohexanecarbonylamino)-4-nitrophenyl]2,2-dimethylthiopropionate;S-[4-cyano-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;S-[4-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;S-[5-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;S-[4-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;S-[4,5-difluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]2,2-dimethylthiopropionate;S-[5-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;bis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl]disulfide; 2-tetrahydrofurylmethyl 2-(1-isopentylcyclohexanecarbonylamino)phenyl disulfide;N-(2-mercaptophenyl)-1-ethylcyclohexanecarboxamide;N-(2-mercaptophenyl)-1-propylcyclohexanearboxamide;N-(2-mercaptophenyl)-1-butylcyclohexanecarboxamide;N-(2-mercaptophenyl)-1-iscbutylcyclohexanecarboxamide;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]cyclo-hexanethiocarboxylate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] thio-benzoate;S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]5-carboxythiopentanoate;S-[2-(1-isopentylcyclohexanecarbonylamino)-4-methylphenyl] thioacetate;bis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl] disulfide;N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide;S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-methylthiopropionate; S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]2-methyl-thiopropionate;S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]1-acetylpiperidine-4-thiocarboxylate;S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl] thioacetate;S-[2-[1-(2-ethylbutyl) cyclohexanecarbonylamino] phenyl]2,2-dimethylthiopropionate; S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino] phenyl] methoxythioacetate;S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]2-hydroxy-2-methylthiopropionate; S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino] phenyl] 4- chlorophenoxythioacetate;S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl] 4-chloro-phenoxythioacetate; andS-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]1-acetyl-piperidine-4-thiocarboxylate, or a prodrug compound, apharmaceutically acceptable salt, a hydrate, or a solvate thereof.
 6. Aprophylactic or therapeutic agent for hyperlipidemia comprising as anactive ingredient the compound as claimed in claim 1, or a prodrugcompound, a pharmaceutically acceptable salt, a hydrate, or a solvatethereof.
 7. A prophylactic or therapeutic agent for hyperlipidemiacomprising as an active ingredient the compound as claimed in claim 2,or a prodrug compound, a pharmaceutically acceptable salt, a hydrate, ora solvate thereof.
 8. A prophylactic or therapeutic agent forhyperlipidemia comprising as an active ingredient the compound asclaimed in claim 3, or a prodrug compound, a pharmaceutically acceptablesalt, a hydrate, or a solvate thereof.
 9. A prophylactic or therapeuticagent for hyperlipidemia comprising as an active ingredient the compoundas claimed in claim 4, or a prodrug compound, a pharmaceuticallyacceptable salt, a hydrate, or a solvate thereof.
 10. A prophylactic ortherapeutic agent for hyperlipidemia comprising as an active ingredientthe compound as claimed in claim 5, oraprodrug compound,apharmaceutically acceptable salt, ahydrate, or a solvate thereof.
 11. Aprophylactic or therapeutic agent for atherosclerosis comprising as anactive ingredient the compound as claimed in claim 1, or a prodrugcompound, apharmaceutically acceptable salt, ahydrate, or a solvatethereof.
 12. A prophylactic or therapeutic agent for atherosclerosiscomprising as an active ingredient the compound as claimed in claim 2,oraprodrug compound, apharmaceutically acceptable salt, ahydrate, or asolvate thereof.
 13. A prophylactic or therapeutic agent foratherosclerosis comprising as an active ingredient the compound asclaimed in claim 3, or a prodrug compound, a pharmaceutically acceptablesalt, a hydrate, or a solvate thereof.
 14. A prophylactic or therapeuticagent for atherosclerosis comprising as an active ingredient thecompound as claimed in claim 4, or a prodrug compound, apharmaceutically acceptable salt, a hydrate, or a solvate thereof.
 15. Aprophylactic or therapeutic agent for atherosclerosis comprising as anactive ingredient the compound as claimed in claim 5, or a prodrugcompound, a pharmaceutically acceptable salt, a hydrate, or a solvatethereof.
 16. A method for inhibition of CETP activity comprisingadministering topatients the compound as claimed in claim 1, or aprodrug compound, a pharmaceutically acceptable salt, a hydrate, or asolvate thereof.
 17. A method for prevention or therapy ofhyperlipidemia comprising administering to patients the compound asclaimed in claim 1, or a prodrug compound, a pharmaceutically acceptablesalt, a hydrate, or a solvate thereof.
 18. A method for prevention ortherapy of atherosclerosis comprising administering to patients thecompound as claimed in claim 1, or a prodrug compound, apharmaceutically acceptable salt, a hydrate, or a solvate thereof.